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EXPERIENCE & REASON |
a Division of Genetics, Birth Defects, and Metabolism, Children's Memorial Hospital, Chicago, Illinois
b Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
c BioMarin Pharmaceutical Inc, Novato, California
ABSTRACT
Our patient with mucopolysaccharidosis type VI received enzyme replacement therapy with recombinant human arylsulfatase B (galsulfase [Naglazyme, BioMarin Pharmaceutical Inc, Novato, CA]) shortly after approval by the US Food and Drug Administration. After 1 month of weekly infusions, the patient developed significant infusion-associated reactions and could not tolerate therapy at the recommended infusion rate. We were able to continue treatment successfully by the addition of steroids to the premedication regimen and by significantly reducing the rate of drug infusion. Over the next several months, the patient's infusion rate was slowly increased and the premedications were weaned. We demonstrate that by significantly reducing the rate of infusions and adjusting the premedication regimen, galsulfase infusions can continue with no additional observance of infusion-associated reactions.
Key Words: MPS VI • management • enzyme replacement therapy • recombinant human arylsulfatase B • galsulfase • Naglazyme
Abbreviations: MPS VI, mucopolysaccharidosis type VI • ASB, arylsulfatase B • GAG, glycosaminoglycan • ERT, enzyme replacement therapy • IAR, infusion-associated reactions
Mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy syndrome is a lysosomal storage disorder that results from a deficiency of the enzyme N-acetylgalactosamine 4-sulfatase, or arylsulfatase B (ASB). The estimated incidence ranges from 1 in 248000 to 1 in 667000 in various populations.1–4 The diagnosis is confirmed on the basis of findings of elevated urine glycosaminoglycans (GAGs) and a deficiency of ASB activity in leukocytes or cultured fibroblasts.5 MPS VI is a highly variable, multisystemic disorder characterized by features commonly observed in other mucopolysaccharide storage (MPS) disorders. The majority of patients present in childhood with hepatosplenomegaly, coarse facial features, corneal clouding, and dysostosis multiplex. Affected patients can have variable short stature, with the severely affected patients reaching an adult height of only 107 to 138 cm.6 Affected patients can develop severe orthopedic complications, including progressive restriction of the joints, carpal tunnel syndrome, kyphoscoliosis, genu valgum, and flexion contractures of the fingers, knees, and elbows. Patients with MPS VI can develop cardiovascular disease such as multivalvular stenosis and regurgitation and cardiomyopathy. Obstructive airway disease is another frequent complication. The cardiac and pulmonary complications are progressive and can lead to death in young adulthood. Neurologic complications observed in MPS VI include hydrocephalus and cervical cord compression caused by atlantoaxial subluxation, abnormal development of the cervical vertebral bodies, and thickening of the dura in the cervical region.6 Unlike other MPS disorders, patients with MPS VI generally do not experience cognitive delays or intellectual decline. Until recently, treatment for MPS VI has mainly involved symptom management. Stem cell/bone marrow transplantation has been performed successfully on some patients, with observed improvement in cardiac symptoms, obstructive sleep apnea, and overall quality of life but little improvement in skeletal manifestations.7 In May 2005, enzyme replacement therapy (ERT) became available for the treatment of MPS VI with the approval of the human recombinant ASB enzyme (galsulfase [Naglazyme, BioMarin Pharmaceutical Inc, Novato, CA]) by the US Food and Drug Administration. Infusions of galsulfase were well tolerated during clinical trials. The majority of infusion-associated reactions (IARs) were judged to be mild to moderate and were managed successfully by interrupting or slowing the rate of infusion and/or by the administration of antihistamines, antipyretics, corticosteroids, or oxygen. Very few serious or severe adverse reactions occurred during the clinical trials. The majority of adverse events that were reported were felt to be related to the patient's underlying condition.
Here we report on a young patient with severe MPS VI who developed a severe IAR within 1 month of initiating therapy.
CASE REPORT
Our patient was a term, normal-sized male infant, born to a nonconsanguineous Hispanic couple of Mexican descent after an uncomplicated pregnancy. He was initially seen at 2 months of age because of the presence of bilateral preauricular pits, a right branchial cleft cyst, a history of a failed auditory brainstem response test, and bilateral middle- and inner-ear anomalies that were revealed on a computed tomography scan of the temporal bones. On physical examination, he was noted to have abundant scalp hair, a prominent nose, preauricular pits bilaterally, a liver edge palpable 1 to 2 cm below the right costal margin, a shawl scrotum, and mild hypotonia with excessive head lag. All growth parameters were between the 25th and 50th percentiles. A unifying diagnosis for the patient's findings was not obvious. Blood chromosome analysis performed at our institution revealed a normal 46,XY karyotype. There were no siblings, and the family history was generally unremarkable. Neither parent had similar clinical features.
At 25 months of age, the patient returned for follow-up and was noted to have short stature with a height of 82.7 cm (<5th percentile), coarse facial features, bilateral epicanthal folds, posteriorly rotated ears, preauricular pits, congestion with noisy breathing, a short neck, shawl scrotum, mild inversion of the left foot, spade-like hands and feet, and a lumbar gibbus deformity (Figs 1 and 2). He was cruising but not yet walking independently and reportedly saying 8 clear words. The findings were suggestive of an MPS disorder, and the diagnosis of MPS VI was confirmed by demonstration of a deficiency of ASB activity in leukocytes, an elevated urine GAG level, and dysostosis multiplex on skeletal survey. The patient subsequently developed typical findings associated with this disorder, including progressive hepatomegaly, severe obstructive sleep apnea that necessitated a tonsillectomy and adenoidectomy, and restricted joint mobility. He had an essentially normal echocardiogram, with suggestion of slightly increased left ventricular size around the time of diagnosis and completely normal repeat echocardiogram at the start of ERT. No corneal clouding was noted during detailed ophthalmology examination.
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The following week, the patient was given 1.25 mg/kg of diphenhydramine intravenously 1 hour before the infusion. The infusion rate was decreased significantly to result in a total duration of 10 hours (12 mL/hour). Approximately 90 minutes into the infusion, the patient developed urticaria over his neck, chest, and back. The infusion was interrupted, and the patient was given 1 mg/kg of diphenhydramine intravenously and 1 mg/kg of methylprednisolone intravenously. After the observed symptoms had resolved completely, the infusion was restarted again at a reduced rate. Shortly after an increase in the rate to 12 mL/hour, the patient again developed urticaria over his lower body, and the infusion was discontinued immediately. The patient was given intravenous diphenhydramine and methylprednisolone, and the symptoms resolved. He was discharged from the hospital in stable condition but only received approximately one third of the galsulfase dose.
On the basis of the patient's reactions to galsulfase at weeks 4 and 5, it was clear that he was not able to tolerate the product with antihistamine premedication alone, even with a lengthened duration of infusion from 4 to 10 hours. Therefore, we devised a protocol by which the patient was premedicated with oral prednisolone (2 mg/kg) the day before each infusion, followed by intravenous methylprednisolone (1 mg/kg) and intravenous diphenhydramine (1.25 mg/kg) 1 hour before each infusion. The rate of infusion was decreased so that galsulfase was initially given over a 16-hour period. The patient also received intravenous diphenhydramine every 4 hours throughout the infusion. After 1 month on the new protocol with no additional IARs observed, the patient's rate of infusion was increased slowly over the next several months, and the premedications were weaned. The patient returned to the typical 4-hour infusion schedule with only an oral antihistamine as premedication 
12 months after the initial IARs were observed. He has had no recurrence of IARs and has shown good response to therapy.
At his most recent follow-up visit at 4 years 6 months of age, his hepatomegaly had resolved, and he had increased range of motion at his elbows and shoulders. He continues to exhibit good linear growth with a height of 87.5 cm recorded near the start of ERT and a height of 90.5 cm obtained 13 months after therapy. His urinary GAG levels have decreased from 546.3 µg of GAG/mg creatinine before the initiation of ERT to 84.1 µg of GAG/mg creatinine. There has been no evidence of corneal clouding. An echocardiogram obtained 14 months after the start of ERT revealed mild mitral valve thickening and mild mitral regurgitation. No treatment other than subacute bacterial endocarditis prophylaxis, when necessary, was recommended by the cardiologist. This is the only new complication associated with MPS VI that the patient has developed since the start of therapy. Although the patient has generally exhibited improvement in symptoms related to his MPS VI, over time he has demonstrated progressive developmental delay with very little progression in expressive language. Given his history of branchial cleft cyst, preauricular pits, and middle- and inner-ear abnormalities, which are not typical of MPS and likely unrelated, we obtained microarray analysis at Signature Genomic Laboratories (Spokane, WA). The analysis revealed a deletion at chromosome 8q13.3, including the EYA1 locus associated with branchio-oto-renal syndrome. This microdeletion likely explains our patient's other findings and developmental delay not attributable to his MPS VI.
DISCUSSION
Efficacy of galsulfase was demonstrated in the clinical trials by improved endurance in patients, as measured by 12-minute walk and 3-minute stair-climb tests, and decreased urinary GAG excretion.8–10 Safety was demonstrated by the lack of severe IARs. Very few serious adverse events occurred during the clinical trials, the majority of which were felt to be attributable to the patients' underlying MPS disorder. The typical adverse events observed during infusion included rash, urticaria, headache, hypotension, nausea, and vomiting. All symptoms resolved with either interruption of therapy, slowing of the rate of infusion, and/or the administration of corticosteroids, antihistamines, and antipyretics.8,10 Given the potential benefits of galsulfase infusions, we believe that every effort should be made to continue ERT even in the face of difficult IARs. We have demonstrated that by significantly reducing the rate of infusions and adjusting the premedication regimen, galsulfase infusions can continue with no additional occurrence of IARs and that decreased infusion rates need not continue indefinitely. We understand, however, that our protocol may not be effective for all patients with MPS VI with complicated IARs and that our patient continues to be at some risk for IARs. Cessation of therapy may need to be considered in rare circumstances for patients who continue to experience severe adverse IARs despite efforts to adjust the infusion schedule and premedication regimen.
FOOTNOTES
Accepted Jul 27, 2007.
Address correspondence to Katherine H. Kim, MS, Children's Memorial Hospital, 2300 Children's Plaza, Box 59, Chicago, IL 60614. E-mail: kkim{at}childrensmemorial.org
The authors have indicated they have no financial relationships relevant to this article to disclose.
REFERENCES
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