Advances in the Treatment of Mucopolysaccharidosis Type I
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《新英格兰医药杂志》
The mucopolysaccharidoses are a group of lysosomal storage diseases caused by a deficiency of enzymes that degrade glycosaminoglycans.1 Mucopolysaccharidosis type I, an autosomal recessive disorder caused by a deficiency of the enzyme -L-iduronidase, is characterized by multisystemic clinical disease. The -L-iduronidase deficiency leads to the progressive accumulation of glycosaminoglycans, resulting in tissue and organ dysfunction. A wide range of clinical presentations, with variations in the severity of symptoms and the extent of central nervous system involvement, is observed in patients with iduronidase deficiency.
In 1919, a German pediatrician named Gertrud Hurler provided the first description of mucopolysaccharidosis type I. Characteristics of the severe form of this disease (Hurler's syndrome) include mental retardation, macrocephaly, corneal clouding, coarse facies, hearing loss, joint stiffness, hepatosplenomegaly, valvular heart disease, airway obstruction, short stature, and a lifespan of less than 10 years. In 1962, an ophthalmologist named Harold Scheie described a mild form of mucopolysaccharidosis (a forme fruste of Hurler's syndrome), which initially became known as mucopolysaccharidosis type V. The patients described by Scheie had many of the physical features associated with Hurler's syndrome but had a normal lifespan, stature, and intelligence.
The nomenclature for the mucopolysaccharidoses was revised after Neufeld and coworkers demonstrated the cause of the lysosomal storage of glycosaminoglycans and made observations that formed the foundation for subsequent attempts to treat these disorders.1 Given these observations, it was initially surprising that Hurler's syndrome and Scheie's syndrome (mucopolysaccharidosis type V) were both attributable to a deficiency of -L-iduronidase. However, it is now well recognized that many persons with such a deficiency do not fit the classic phenotypes — Hurler's, Hurler–Scheie, or Scheie's syndrome — but rather represent a spectrum of phenotypic variability. In view of this variability, it is more appropriate to diagnose mucopolysaccharidosis type I in all patients with -L-iduronidase deficiency, reserving the designation of Hurler's syndrome for the severe form of the disease.
Fratantoni and colleagues demonstrated that in coculture, cells from persons with mucopolysaccharidosis types I and II were able to correct glycosaminoglycan storage through the release of "correction factors" that were later recognized as the deficient lysosomal enzymes.2 The subsequent discovery of a mannose-6-phosphate–recognition system established the biochemical basis for the cellular uptake of lysosomal enzymes.3 Receptor-mediated endocytosis occurs when a lysosomal enzyme with a mannose-6-phosphate residue binds to the mannose-6-phosphate receptor located in the clathrin-coated pit on the cell surface (see Figure).
Figure. Transport of a Lysosomal Enzyme in a Normal Cell and Correction of Storage in the Cell of a Patient with Mucopolysaccharidosis.
The mannose-6-phosphate–recognition signal is added to the lysosomal enzyme precursor in the late-Golgi compartments, where enzyme modified by mannose-6-phosphate binds to mannose-6-phosphate receptors. The enzyme–receptor complex is packaged into a transport carrier vesicle and delivered to early endosomes in which low pH promotes the dissociation of the enzyme from the receptor. The enzyme is then delivered to the mature lysosome, and the mannose-6-phosphate receptor is recycled to the Golgi apparatus. A small amount of the mannose-6-phosphate–modified enzyme escapes capture by the mannose-6-phosphate receptors and is released into the extracellular space. This enzyme can be recaptured by binding to a mannose-6-phosphate receptor in a clathrin-coated pit on the cell surface. In a patient who has undergone hematopoietic stem-cell transplantation, enzyme released from a donor-derived stem cell can be taken up by a mucopolysaccharidosis cell, which corrects aberrant glycosaminoglycan storage.
Mucopolysaccharidoses are ideal candidates for treatment because there is a high-affinity uptake mechanism for lysosomal enzymes, and residual enzyme activity of 1 to 2 percent is all that is needed to prevent storage disorders. The initial attempts at enzyme replacement (such as plasma and white-cell infusions, skin-fibroblast transplantation, or amnion-membrane implantation) failed because inadequate amounts of enzyme were delivered or the enzyme was missing the mannose-6-phosphate–recognition marker. Hematopoietic stem-cell transplantation and, more recently, the use of recombinant enzymes produced through genetic engineering have overcome these obstacles. For optimal benefit, any intervention must occur before the progressive accumulation of glycosaminoglycans leads to irreversible tissue and organ damage. As treatment options for mucopolysaccharidoses improve, the screening of newborns may be essential for timely diagnosis and the initiation of treatment before the onset of irreversible damage.
The first successful bone marrow transplantation for Hurler's syndrome was reported in 1981. More than 300 transplantations — initially of bone marrow and now of umbilical-cord blood — have been performed worldwide in patients with Hurler's syndrome. Hematopoietic stem-cell transplantation has been shown to be an effective treatment for the somatic disease in mucopolysaccharidosis type I, except for bone and eye disease. Cord-blood transplantation appears to be as effective as bone marrow transplantation in Hurler's syndrome, as demonstrated by Staba et al. in this issue of the Journal (pages 1960–1969). After successful hematopoietic stem-cell transplantation in a patient with mucopolysaccharidosis type I, the life expectancy is increased, hepatosplenomegaly resolves, cardiac disease is stabilized, and there is improvement in the range of motion of joints, airway disease, and hearing. Because of the minimal effect of bone marrow transplantation on the progression of the skeletal disease in mucopolysaccharidosis type I, multiple orthopedic procedures are typically required to maintain function. Whether cord-blood transplantation slows or prevents the progression of the bone disease in patients with this condition remains to be established.
The observed benefit of hematopoietic stem-cell transplantation for the central nervous system in patients with mucopolysaccharidosis type I has ranged from stabilization and the prevention of neurologic decline to a minimal improvement at best in children who have neurologic disease at the time of transplantation. The microglial cells in the brain originate in the bone marrow and are believed to be the source of iduronidase enzyme in the brain after a successful hematopoietic stem-cell transplantation. Multiple factors such as the patient's age at the time of transplantation, the donor's status (ideally, noncarrier of a pathogenic iduronidase mutation), and the degree of central nervous system involvement may contribute to the outcome with regard to the central nervous system.
Hematopoietic stem-cell transplantation is now the treatment of choice for a child with Hurler's syndrome who is younger than two years of age and has minimal or no central nervous system disease. Although this treatment can affect the neurologic disease in Hurler's syndrome, transplantation is currently not recommended for the severe form of Hunter's syndrome (mucopolysaccharidosis type II) or Sanfilippo's syndrome (mucopolysaccharidosis type III), since neurologic preservation has not been observed in either disorder. The explanation for the lack of a central nervous system benefit in these two forms of the disorder is unclear.
Enzyme-replacement therapy with the use of recombinant -L-iduronidase (laronidase), which has recently been approved by the Food and Drug Administration, is recommended for patients with the milder or attenuated forms of mucopolysaccharidosis type I and for patients with neurologic impairment. In the latter group of patients, because of the lack of a central nervous system benefit of hematopoietic stem-cell transplantation and the high risk of complications or death associated with transplantation (at least 15 to 20 percent), infusions of recombinant enzyme are a safer alternative for treating the somatic disease and improving the quality of life. Intravenously administered enzyme is not expected to cross the blood–brain barrier and affect central nervous system disease.
The administration of recombinant enzyme 6 to 12 weeks before and up to 3 months after hematopoietic stem-cell transplantation has been proposed as a means of improving engraftment and stabilizing the clinical disease before the onset of endogenous enzyme production by the donor cells. The long-term use of enzyme-replacement therapy in patients with mucopolysaccharidosis type I whose transplants are stably engrafted should be assessed to determine whether the administration of additional exogenous enzyme is beneficial.
When mucopolysaccharidosis is diagnosed in a patient, the family and primary care providers will immediately encounter an unfamiliar realm of medical knowledge regarding the implications of the diagnosis, as well as the treatment options of hematopoietic stem-cell transplantation and enzyme-replacement therapy. Adequate counseling on these options, including the risks and benefits associated with each, is crucial for those embarking on this difficult, possibly time-sensitive decision-making process, which is made more challenging by the emotionally charged experience of receiving the diagnosis.
Dr. Muenzer reports having received consulting fees and research support from Transkaryotic Therapies, lecture fees from Genzyme, and consulting fees from Biomarin Pharmaceuticals.
Source Information
From the Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill.
References
Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. Vol. 3. New York: McGraw-Hill, 2001:3421-52.
Fratantoni JC, Hall CW, Neufeld EF. Hurler and Hunter syndromes: mutual correction of the defect in cultured fibroblasts. Science 1968;162:570-572.
Ghosh P, Dahms NM, Kornfeld S. Mannose 6-phosphate receptors: new twists in the tale. Nat Rev Mol Cell Biol 2003;4:202-212.(Joseph Muenzer, M.D., Ph.)
In 1919, a German pediatrician named Gertrud Hurler provided the first description of mucopolysaccharidosis type I. Characteristics of the severe form of this disease (Hurler's syndrome) include mental retardation, macrocephaly, corneal clouding, coarse facies, hearing loss, joint stiffness, hepatosplenomegaly, valvular heart disease, airway obstruction, short stature, and a lifespan of less than 10 years. In 1962, an ophthalmologist named Harold Scheie described a mild form of mucopolysaccharidosis (a forme fruste of Hurler's syndrome), which initially became known as mucopolysaccharidosis type V. The patients described by Scheie had many of the physical features associated with Hurler's syndrome but had a normal lifespan, stature, and intelligence.
The nomenclature for the mucopolysaccharidoses was revised after Neufeld and coworkers demonstrated the cause of the lysosomal storage of glycosaminoglycans and made observations that formed the foundation for subsequent attempts to treat these disorders.1 Given these observations, it was initially surprising that Hurler's syndrome and Scheie's syndrome (mucopolysaccharidosis type V) were both attributable to a deficiency of -L-iduronidase. However, it is now well recognized that many persons with such a deficiency do not fit the classic phenotypes — Hurler's, Hurler–Scheie, or Scheie's syndrome — but rather represent a spectrum of phenotypic variability. In view of this variability, it is more appropriate to diagnose mucopolysaccharidosis type I in all patients with -L-iduronidase deficiency, reserving the designation of Hurler's syndrome for the severe form of the disease.
Fratantoni and colleagues demonstrated that in coculture, cells from persons with mucopolysaccharidosis types I and II were able to correct glycosaminoglycan storage through the release of "correction factors" that were later recognized as the deficient lysosomal enzymes.2 The subsequent discovery of a mannose-6-phosphate–recognition system established the biochemical basis for the cellular uptake of lysosomal enzymes.3 Receptor-mediated endocytosis occurs when a lysosomal enzyme with a mannose-6-phosphate residue binds to the mannose-6-phosphate receptor located in the clathrin-coated pit on the cell surface (see Figure).
Figure. Transport of a Lysosomal Enzyme in a Normal Cell and Correction of Storage in the Cell of a Patient with Mucopolysaccharidosis.
The mannose-6-phosphate–recognition signal is added to the lysosomal enzyme precursor in the late-Golgi compartments, where enzyme modified by mannose-6-phosphate binds to mannose-6-phosphate receptors. The enzyme–receptor complex is packaged into a transport carrier vesicle and delivered to early endosomes in which low pH promotes the dissociation of the enzyme from the receptor. The enzyme is then delivered to the mature lysosome, and the mannose-6-phosphate receptor is recycled to the Golgi apparatus. A small amount of the mannose-6-phosphate–modified enzyme escapes capture by the mannose-6-phosphate receptors and is released into the extracellular space. This enzyme can be recaptured by binding to a mannose-6-phosphate receptor in a clathrin-coated pit on the cell surface. In a patient who has undergone hematopoietic stem-cell transplantation, enzyme released from a donor-derived stem cell can be taken up by a mucopolysaccharidosis cell, which corrects aberrant glycosaminoglycan storage.
Mucopolysaccharidoses are ideal candidates for treatment because there is a high-affinity uptake mechanism for lysosomal enzymes, and residual enzyme activity of 1 to 2 percent is all that is needed to prevent storage disorders. The initial attempts at enzyme replacement (such as plasma and white-cell infusions, skin-fibroblast transplantation, or amnion-membrane implantation) failed because inadequate amounts of enzyme were delivered or the enzyme was missing the mannose-6-phosphate–recognition marker. Hematopoietic stem-cell transplantation and, more recently, the use of recombinant enzymes produced through genetic engineering have overcome these obstacles. For optimal benefit, any intervention must occur before the progressive accumulation of glycosaminoglycans leads to irreversible tissue and organ damage. As treatment options for mucopolysaccharidoses improve, the screening of newborns may be essential for timely diagnosis and the initiation of treatment before the onset of irreversible damage.
The first successful bone marrow transplantation for Hurler's syndrome was reported in 1981. More than 300 transplantations — initially of bone marrow and now of umbilical-cord blood — have been performed worldwide in patients with Hurler's syndrome. Hematopoietic stem-cell transplantation has been shown to be an effective treatment for the somatic disease in mucopolysaccharidosis type I, except for bone and eye disease. Cord-blood transplantation appears to be as effective as bone marrow transplantation in Hurler's syndrome, as demonstrated by Staba et al. in this issue of the Journal (pages 1960–1969). After successful hematopoietic stem-cell transplantation in a patient with mucopolysaccharidosis type I, the life expectancy is increased, hepatosplenomegaly resolves, cardiac disease is stabilized, and there is improvement in the range of motion of joints, airway disease, and hearing. Because of the minimal effect of bone marrow transplantation on the progression of the skeletal disease in mucopolysaccharidosis type I, multiple orthopedic procedures are typically required to maintain function. Whether cord-blood transplantation slows or prevents the progression of the bone disease in patients with this condition remains to be established.
The observed benefit of hematopoietic stem-cell transplantation for the central nervous system in patients with mucopolysaccharidosis type I has ranged from stabilization and the prevention of neurologic decline to a minimal improvement at best in children who have neurologic disease at the time of transplantation. The microglial cells in the brain originate in the bone marrow and are believed to be the source of iduronidase enzyme in the brain after a successful hematopoietic stem-cell transplantation. Multiple factors such as the patient's age at the time of transplantation, the donor's status (ideally, noncarrier of a pathogenic iduronidase mutation), and the degree of central nervous system involvement may contribute to the outcome with regard to the central nervous system.
Hematopoietic stem-cell transplantation is now the treatment of choice for a child with Hurler's syndrome who is younger than two years of age and has minimal or no central nervous system disease. Although this treatment can affect the neurologic disease in Hurler's syndrome, transplantation is currently not recommended for the severe form of Hunter's syndrome (mucopolysaccharidosis type II) or Sanfilippo's syndrome (mucopolysaccharidosis type III), since neurologic preservation has not been observed in either disorder. The explanation for the lack of a central nervous system benefit in these two forms of the disorder is unclear.
Enzyme-replacement therapy with the use of recombinant -L-iduronidase (laronidase), which has recently been approved by the Food and Drug Administration, is recommended for patients with the milder or attenuated forms of mucopolysaccharidosis type I and for patients with neurologic impairment. In the latter group of patients, because of the lack of a central nervous system benefit of hematopoietic stem-cell transplantation and the high risk of complications or death associated with transplantation (at least 15 to 20 percent), infusions of recombinant enzyme are a safer alternative for treating the somatic disease and improving the quality of life. Intravenously administered enzyme is not expected to cross the blood–brain barrier and affect central nervous system disease.
The administration of recombinant enzyme 6 to 12 weeks before and up to 3 months after hematopoietic stem-cell transplantation has been proposed as a means of improving engraftment and stabilizing the clinical disease before the onset of endogenous enzyme production by the donor cells. The long-term use of enzyme-replacement therapy in patients with mucopolysaccharidosis type I whose transplants are stably engrafted should be assessed to determine whether the administration of additional exogenous enzyme is beneficial.
When mucopolysaccharidosis is diagnosed in a patient, the family and primary care providers will immediately encounter an unfamiliar realm of medical knowledge regarding the implications of the diagnosis, as well as the treatment options of hematopoietic stem-cell transplantation and enzyme-replacement therapy. Adequate counseling on these options, including the risks and benefits associated with each, is crucial for those embarking on this difficult, possibly time-sensitive decision-making process, which is made more challenging by the emotionally charged experience of receiving the diagnosis.
Dr. Muenzer reports having received consulting fees and research support from Transkaryotic Therapies, lecture fees from Genzyme, and consulting fees from Biomarin Pharmaceuticals.
Source Information
From the Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill.
References
Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. Vol. 3. New York: McGraw-Hill, 2001:3421-52.
Fratantoni JC, Hall CW, Neufeld EF. Hurler and Hunter syndromes: mutual correction of the defect in cultured fibroblasts. Science 1968;162:570-572.
Ghosh P, Dahms NM, Kornfeld S. Mannose 6-phosphate receptors: new twists in the tale. Nat Rev Mol Cell Biol 2003;4:202-212.(Joseph Muenzer, M.D., Ph.)