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After reading the article you should be able to:

1. Describe the epidemiology of the lysosomal storage diseases (LSDs).
2. Compare and contrast the signs and symptoms of the various LSDs.
3. Discuss the enzyme replacement therapies (ERTs) employed to treat the LSDs.

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By LINDA P. MANWARING, MS, PATRICIA A. JAMERSON, RN, PhD, and RACHEL SLAUGH, MS

LINDA MANWARING is a genetic counselor at Washington University School of Medicine in St. Louis, MO. PATRICIA JAMERSON is a nurse scientist researcher at St. Louis Children’s Hospital. RACHEL SLAUGH is a genetic counselor at St. John’s Mercy Medical Center, St. Louis. PATRICIA JAMERSON and RACHEL SLAUGH have no financial relationships to disclose. LINDA MANWARING reports that she has received research support from Genzyme Corp. and Shire. EDITOR: KATHLEEN A. MOORE, RN, BS

Lysosomal storage diseases can’t be cured, but enzyme replacement therapy offers some patients hope.

Lysosomal storage diseases (LSDs) are a group of more than 40 inherited disorders in which one of the enzymes responsible for breaking down macromolecules within the cells' lysosomes is missing or deficient. Each of the LSDs is caused by a mutation in a gene responsible for providing directions to make a specific enzyme. Without the enzyme, the corresponding macromolecule, or substrate, then accumulates in the cells, causing problems of varying severity—and in some cases, death.

LSDs are rare disorders and are diagnosed by enzyme studies, in most instances. Collectively, they occur in one in 7,700 live births.¹ As the box on page 35 explains, most have an autosomal recessive inheritance pattern and thus affect males and females at equal rates. Others are carried on the X chromosome and predominantly affect males.

At present, LSDs are incurable. Through DNA recombination, however, companies now can manufacture several of these missing enzymes for administration to patients in need. This treatment, known as enzyme replacement therapy (ERT), slows disease progression and ameliorates symptoms in some of these conditions, offering patients and families hope. We'll review the LSDs managed with ERT, and the nursing considerations related to this type of treatment.

The most well-known of the LSDs

LSDs are classified according to the substrate that accumulates in the cell as sphingolipidoses, mucopolysaccharide disorders, or glycogen storage disorders, for example. The first LSD for which ERT became available, and the most familiar, is Gaucher disease, a sphingolipid storage disorder in which the lipid glucocerebroside accumulates in macrophage cells in the liver, spleen, and bone marrow.² Buildup in the liver and spleen can lead to hepatosplenomegaly, a massively distended abdomen, and hypersplenism leading to anemia and thrombocytopenia. Accumulation in the bone marrow can cause osteopenia, osteonecrosis, and bone pain, and may necessitate early joint replacement.²

In the United States, the most common form of Gaucher disease is Type 1. Its prevalence is highest among individuals of Ashkenazi Jewish ancestry. Diagnosis of Type 1 may occur any time from early childhood to late in life. Progression of the disease is variable, with some individuals never developing symptoms.²

Before ERT, a splenectomy was done to alleviate splenomegaly and thrombocytopenia. Today, imiglucerase (Cerezyme), which received U. S. Food and Drug Administration (FDA) approval for ERT in 1991, reduces glucocerebroside accumulation in the liver and spleen, improves anemia and thrombocytopenia, and helps stabilize bone marrow disease in patients with Type 1 Gaucher disease.²

Another sphingolipid disorder is Fabry—or Anderson-Fabry—disease, which is caused by a deficiency of alpha-galactosidase A. Without this enzyme, globotriaosyl-ceramide (GL3 or GB3) collects in the visceral organs and blood vessel walls, damaging the heart, kidneys, and brain.³ An X-linked condition, Fabry disease affects males more frequently—and generally more severely—than females.

Signs and symptoms often begin in adolescence and include intense burning in the hands and feet; impaired sweating; intolerance to heat and cold; and angiokeratomas (raised, dark red or purple, non-blanching lesions) from the abdomen to the knees. An eye exam may reveal corneal whirling (a starburst pattern) from the deposit of GL3 in the blood vessels of the eyes; this does not affect vision. Accumulation of GL3 in the ganglia of the bowels may result in abnormal GI motility, causing early satiety, diarrhea, and abdominal cramping after eating.

Late complications include cardiac abnormalities, stroke, and hearing loss, and reduced kidney function requiring dialysis and kidney transplantation. Men with untreated Fabry disease typically die in their 30s or 40s of renal failure or cardiovascular or cerebrovascular disease.³

Before ERT, Fabry disease was managed with symptom-specific treatment for pain and organ involvement. In 2003, the FDA approved agalsidase beta (Fabrazyme), which decreases pain, improves sweating, and reduces the amount of GL3 in the kidneys, heart, and skin.³

The broad spectrum of MPS I

Mucopolysaccharidosis (MPS) I is caused by a deficiency of glycosidase alpha-L-iduronidase, which leads to the accumulation of mucopolysaccharides, or glycosaminoglycans (GAGs).⁴ The most severe form is Hurler syndrome, the mildest is Scheie syndrome, and intermediate forms are called Hurler-Scheie syndrome.

Children with classic Hurler syndrome develop signs and symptoms in the first year of life. Early signs are kyphosis (curvature of the upper spine) and gibbus (hunchback). Other manifestations include hepatosplenomegaly, corneal clouding, deafness, cardiac complications, hernias, and airway obstruction. An affected individual may have coarse features, including full lips, widely spaced eyes, thickened gums, and a large head with frontal prominence. Hydrocephalus is common, and joint contractures and carpal tunnel syndrome are inevitable.

Hurler syndrome is progressive and causes mental retardation. Initially, children with the disease may grow and develop normally, but as GAGs accumulate, they experience delays and even regression. Untreated Hurler syndrome typically results in death early in the second decade of life. The cause is usually respiratory insufficiency from upper airway obstruction or reduced lung capacity.⁴

Scheie syndrome is most frequently diagnosed during the teen or adult years, following the development of joint contractures. Affected individuals often need numerous surgical procedures for carpal tunnel syndrome and other joint problems.⁴ Other manifestations are mild hepatosplenomegaly and corneal clouding. Because individuals with Scheie syndrome have some enzyme activity, they don't have the neurological involvement seen in Hurler syndrome, and their lifespan is normal. As adults, however, they're at risk for aortic valve stenosis and regurgitation.

Treatment for MPS I depends on disease severity and the patient's age at diagnosis. Bone marrow transplantation (BMT) for severe MPS I, performed before age two, prolongs survival and allows for normal or near-normal cognitive development.⁵ Children who've undergone BMT for MPS I will continue to have skeletal problems such as scoliosis, carpal tunnel syndrome, and joint contractures.

Laronidase (Aldurazyme) was approved in 2003 for Hurler-Scheie and Scheie syndromes. Reportedly, it improves forced vital capacity, increases the distance walked during a six-minute walk test, decreases hepatosplenomegaly, and reduces the number of apnea events per night.⁶ Since there's no evidence that it prevents neurological complications, its long-term use is not recommended for classic Hurler syndrome. Its benefit to children awaiting BMT is being studied.

Three more LSDs helped by ERT

A deficiency of the iduronate-2-sulfatase enzyme causes the LSD known as Hunter syndrome, or MPS II. The disease affects males predominantly. Females may be carriers but, except in rare cases, do not manifest symptoms.

The clinical features of Hunter syndrome vary. Early growth and development usually are normal, with diagnosis occurring around two years of age. The most common findings are short stature, large skull, coarse facial features, hirsutism (excess body hair), progressive hearing loss, joint contractures, skeletal deformities, cardiomegaly, valve disorders, progressive airway obstruction, and abdominal protuberance from hepatosplenomegaly.

Severely affected individuals experience neurological deterioration, behavioral disorders, and mental retardation. Death usually occurs during the second decade of life, although some patients survive into their 50s.⁴ Approved in 2006, idursulfase (Elaprase) improves walking and pulmonary function in patients with milder manifestations of the disease.⁷

Two other LSDs for which ERT is showing promise are mucopolysaccharidosis VI and Pompe syndrome. In MPS VI, also known as Maroteaux-Lamy syndrome, a deficiency in N-acetylgalactosamine 4-sulfatase can be managed with galsulfase (Naglazyme), approved 2003. Studies indicate that it decreases urinary GAG levels and improves walking and stair-climbing ability.^8,9

Pompe syndrome is a glycogen storage disorder with a particularly high incidence in African-Americans.¹⁰ Clinical trials of ERT using alglucosidase alfa (Myozyme) for patients with infantile-onset Pompe disease—its most severe form—have shown improvement in survival rates and in cardiac and skeletal muscle function.¹⁰ Before ERT, babies with classic infantile-onset Pompe disease often died within the first year of life from cardio-respiratory failure.¹⁰

Your role in enzyme replacement

The table on page 36 lists several of the products used for ERT. Most require refrigeration at temperatures between 36° F (2.3? C) and 46° F (7.7? C) and must be brought to room temperature before reconstitution and dilution. With proper storage and preparation, ERT remains stable for 24 hours. Avoid vigorous shaking or agitation of the vial and solution bag. For the infusion, use a 0.2-micron inline filter; generally, filter needles are not recommended.

Dosing is individualized, based on the individual's weight, the desired treatment goals, and how well the patient tolerates the treatment. The frequency and rate of administration vary with the agent. With some agents, prophylactic antipyretics and antihistamines may be necessary.

The adverse effects of ERT are minimal, but anaphylaxis is possible, so monitor the patient throughout the infusion. Giving the solution at a rate faster than that recommended by the manufacturer increases the risk of adverse effects. In the event of an infusion-associated reaction, it typically is advised to temporarily stop the infusion and notify the physician, who may have you administer an antipyretic and/or antihistamine before resuming the infusion at a slower rate. Due to the risk for reactions, treatment typically is administered for the first several months in a hospital infusion setting rather than home health.

To maintain the benefit of ERT, patients must continue the treatment for life, and this can present problems. Ongoing treatment may require the repeated insertion of IV catheters, which is often difficult, particularly in patients with MPS I and II, because of thickened skin from glycosaminoglycan accumulation. The need for repeated IV insertion may warrant placement of a central venous catheter.

Working to ensure patient compliance

Quality of life is an issue for patients receiving ERT. Since infusions typically take two to four hours, patients and their parents may have to miss half a day of school or work for each treatment session. Children who miss school for ERT may need to complete their work outside the classroom, without the aid of their teacher. For some, this can significantly affect educational performance. ERT administered in the home may allow for greater flexibility in scheduling than ERT provided at an outpatient facility.

Another concern is ERT's cost, which may exceed $400,000 a year. Although it typically is covered by insurance, out-of-pocket expense can be significant, depending on insurance deductibles.

Given these obstacles, compliance can be an issue, especially as symptoms subside, and patients and families no longer see new or additional improvement. Those who began treatment as children and never experienced the more significant consequences of their disease may not perceive themselves as sick and thus may not recognize the need for treatment. And patients who don't see the degree of improvement they'd expected may be tempted to discontinue ERT.

Developing a relationship with the patient and family can help in overcoming these obstacles. Remind patients of ERT's proven benefits. When possible, schedule infusions for days and times that are convenient for the patient and family. If appropriate, arrange for in-home infusions. When necessary, help families explore other insurance and payment options.

Knowledge of lysosomal diseases will become increasingly important as states begin to screen newborns for a subset of these disorders.¹ In the meantime, ERT continues to provide relief to families affected by LSDs that, prior to the availability of enzyme replacement, had been devastating. Nurses are essential to the safe administration of this treatment, and to the compliance and long-term follow-up that's crucial to establishing its efficacy.

REFERENCES

1. Meikle, P. J., Grasby, D. J., et al. (2006). Newborn screening for lysosomal storage disorders. Mol Genet Metab, w(4), 307.

2. Charrow, J., Esplin, J.A., et al. (1998). Gaucher disease: Recommendations on diagnosis, evaluation, and monitoring. Arch Intern Med, 158(16), 1754.

3. Desnick, R. J., Brady, R., et al. (2003). Fabry disease, an under-recognized multisystemic disorder: Expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med, 138(4), 338.

4. Neufeld, E. F., & Muenzer, J. (2001). The Mucopolysaccharidoses. In C. R. Scriver, A. L. Beaudet, et al. (Eds.), The metabolic & molecular bases of inherited disease (8th edition, pp. 3421-3452). New York: McGraw-Hill.

5. Peters, C., Steward, C. G., et al. (2003). Hematopoietic cell transplantation for inherited metabolic diseases: An overview of outcomes and practice guidelines. Bone Marrow Transplantation, 31(4), 229.

6. Kakkis, E. D., Muenzer, J., et al. (2001). Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med, 344(3), 182.

7. Muenzer, J., Wraith, J. E., et al. (2006). A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis type II (Hunter syndrome). Genet Med, 8(8), 465.

8. Harmatz, P., Whitley, C. B., et al. (2004). Enzyme replacement therapy in mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). J Pediatr, 144(5), 574.

9. Harmatz, P., Ketteridge, D., et al. (2005). Direct comparison of measures of endurance, mobility, and joint function during enzyme-replacement therapy of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): Results after 48 weeks in a phase 2 open-label clinical study of recombinant human N-acetylgalactosamine 4-sulfatase. Pediatrics, 115(6), e681.

10. Kishnani, P. S., Steiner, R. D., et al. (2006). Pompe disease diagnosis and management guideline. Genet Med, 8(5), 267.

Genetics 101

Most LSDs are inherited in an autosomal recessive manner, which means that both copies of the gene responsible for making the enzyme must have the mutation for the disease to occur. Parents of an affected individual are considered carriers because each has one copy of the mutated gene. When both parents are carriers, each child has a one-in-four chance of inheriting the condition. When one parent has the disease, all of the children will be carriers but usually will not have the disease—unless the other parent carries the gene, too. Autosomal recessive diseases affect males and females equally.

Two LSDs, Fabry disease and Hunter syndrome, are inherited in an X-linked manner. Because X-linked disorders are carried on the X chromosome, they frequently affect only men. Since men have only one X chromosome, a mutation in a gene on that chromosome renders the gene ineffective, and the male inherits the disease. Women have two X chromosomes, so a genetic mutation on only one often causes no symptoms, or it results in less-severe symptoms than in a male. The sons of a male with an X-linked disorder won't inherit the mutation, but all of his daughters will, making them carriers. Each child of a carrier female has a 50% chance of inheriting the mutation.

Treating LSDs

Listed below are the products approved for ERT, along with their indications, dosage information, and most common infusion-related reactions. Fever, rash, and headache can occur with any of the agents. Studies have not addressed potential teratogenic effects of ERT.

Click here to view full-size graphic

Sources: 1. Food and Drug Administration. "Aldurazyme." 2008. http://www.fda.gov/CDER/foi/label/2003/larobio043003LB.pdf (19 June 2008). 2. Food and Drug Administration. "Cerezyme." 2008. http://www.fda.gov/cder/foi/label/2002/20367slr055_Cerezyme_lbl.pdf (19 June 2008). 3. Drugs.com. "Elaprase." 2008. http://www.drugs.com/ppa/idursulfase.html (19 June 2008). 4. Food and Drug Administration. "Fabrazyme." 2008. http://www.fda.gov/cder/foi/label/2003/agalgen042403LB.pdf (19 June 2008). 5. Drugs.com. "Myozyme." 2008.http://www.drugs.com/ppa/alglucosidase-alfa.html (19 June 2008). 6. Drugs.com. "Naglazyme." 2008. http://www.drugs.com/ppa/galsulfase.html (19 June 2008). 7. MedlinePlus. Drugs and Supplements. 2008. http://www.nlm.nih.gov/medlineplus/druginformation.html (19 June 2008).