Lysosomal storage disorders are a group of diseases that are characterized by accumulation of waste products in the lysosomes. These disorders are rare inborn errors of metabolism, with a combined incident of 1 in 1500 to 7000 live births. Lysosomal enzymes break down macromolecules, either those from the cell itself (eg, when cellular structural components are being recycled) or those acquired outside the cell. (The Merck Manual [2012 April 26] <www.merckmanual.com>.)
Treatment of lysosomal storage disease is by enzyme replacement with placental or recombinant glucocerebrosidase that is effective in types I and III; there is no treatment for type II. The replacement enzyme is modified for delivery to the lysosomes.
Idursulfase (Elaprase) is the first drug approved by the U.S. Food and Drug Administration (FDA) for Hunter’s syndrome. Elaprase was approved as an orphan drug used to treat, prevent, or diagnose a rare disease; it is manufactured using recombinant DNA technology. The result is the production of an enzyme that is almost identical to the enzyme produced in the human body. Treatment allows the body to uptake the enzyme into cellular lysosomes, thereby aiding in the catabolism of accumulated glycosaminoglycans (GAGs).
Hunter syndrome, also known as mucopolysaccharide metabolism disorder with iduronate-2-sulfatase deficiency, is a rare X-linked recessive, inherited and potentially fatal disorder in children. This syndrome has variable manifestations exhibiting mainly microcephaly, characteristic facies, mental retardation/intellectual disability, short stature, acral skeletal anomalies with occasional craniosynostosis and congenital heart defects. Clinical characteristics are similar to those in alpha-L-iduronidase (MPS I), except for the absence of corneal clouding and slower progression of the course of disease and central nervous system deterioration. Retinal degeneration may occur, but the cornea usually remains clear. Appearance is normal at birth with excessive growth taking place during the first two years of life. Two types are recognized:
- A severe form (MPS IIA) which is characterized mainly by mental retardation/intellectual disability and progressive physical deterioration and early death, AND
- A mild form (MPS IIB) in which patients may survive into adulthood.
MPS IIA usually occurs between two and four years of age with progressive deterioration, chronic diarrhea, recurrent ear infections, hearing impairment, communicating hydrocephalus with increased intracranial pressure, and death at about 10 to 15 years of age. Obstructive airway disease, cardiac valvular dysfunction, myocardial thickening, pulmonary hypertension, coronary disease, and myocardial infarction may be superimposed. MPS IIB is milder with preservation of intelligence. The symptoms usually include hearing impairment, carpal tunnel syndrome, joint stiffness, discrete corneal opacities, and papilledema. Death may occur in early adulthood, usually from airway obstruction or cardiac failure. Only 500 patients in the United States are believed to have the disease, which affects mostly boys. Hunter syndrome is diagnosed in approximately one in 65,000 to132,000 births.
Alglucosidase alfa (Myozyme) is the first drug approved by the FDA to treat infantile-onset Pompe disease. Myozyme has orphan drug status and has been shown to improve ventilator-free survival in patients with infantile-onset Pompe disease as compared to untreated historical control, where use of Myozyme in patients with other forms of Pompe disease has not been adequately studied to assure safety and efficacy.
Myozyme provides an exogenous source of alpha-glucosidase (GAA). Binding to mannose-6-phosphate receptors on the cell surface has been shown to occur via carbohydrate groups on the GAA molecule, after which it is internalized and transported into lysosomes, where it undergoes proteolytic cleavage that results in increased enzymatic activity. It then exerts enzymatic activity in cleaving glycogen.
Pompe disease is a rare inherited and often fatal disorder that disables the heart and muscles. It is caused by mutations in a gene that makes an enzyme called GAA. Normally the body uses GAA to break down glycogen, a stored form of sugar used for energy. But in Pompe disease, mutations in the GAA gene reduce or completely eliminate this essential enzyme. Excessive amounts of glycogen accumulate everywhere in the body, but the cells of the heart and skeletal muscles are the most seriously affected. Researchers have identified up to 70 different mutations in the GAA gene that cause the symptoms of Pompe disease, which can vary widely in terms of age of onset and severity. The severity of the disease and the age of onset are related to the degree of enzyme deficiency. The prognosis for individuals with Pompe disease varies according to the onset and severity of symptoms. Without treatment the disease is particularly lethal in infants and young children.
Infantile Pompe disease is the result of complete or near complete deficiency of GAA. Symptoms usually begin in the first months of life, with feeding problems, poor weight gain, severe lack of muscle tone, weakness, and an enlarged heart and liver. Respiratory difficulties are often complicated by lung infections. The heart is grossly enlarged. Mental function is not affected. More than half of all infants with Pompe disease also have enlarged tongues. Most babies with Pompe disease die from cardiac or respiratory complications before the age of two.
Alglucosidase alfa (Lumizyme) was approved by the FDA in 2010 for use in patients eight years and older with late-onset Pompe disease that has not shown evidence of cardiac hypertrophy. The safety and efficacy of Lumizyme has not been evaluated in infantile-onset or in patients less than eight years of age with late (non-infantile) onset Pompe disease. Late-onset Pompe disease differs from infantile principally because of the lack of cardiac involvement and it is only partially deficient of GAA. Juvenile onset symptoms appear in early to late childhood and include progressive weakness in the respiratory muscles, and lower limbs, and contribute to exercise intolerance. Adult onset involves muscle weakness and wasting of respiratory muscles in the trunk, lower limbs, and diaphragm. Intellect is not affected. A small number of adult patients live without major symptoms or limitations. The prognosis for individuals with Pompe disease varies according to the onset and severity of symptoms. Without treatment, the disease is particularly lethal in infants and young children.
Both Myozyme and Lumizyme are manufactured by Genzyme Corporation, but at different manufacturing sites using different manufacturing processes, under separate biologic license applications. Lumizyme is only available through a restricted distribution program called Lumizyme ACE (Alglucosidase Alfa Control and Education) to ensure its use is restricted to the correct patient group.
NOTE: Anaphylactoid reactions, which may be life threatening, have been observed in some patients during Elaprase, Myozyme or Lumizyme infusions. Therefore, appropriate medical support should be readily available when Elaprase, Myozyme or Lumizyme is administered. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring.