Mucopolysaccharidoses Types I-VII Treatment & Management

Updated: Apr 14, 2016
  • Author: Janette Baloghova, MD, PhD; Chief Editor: Dirk M Elston, MD  more...
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Treatment

Medical Care

No cure exists for mucopolysaccharidosis; current treatment is symptomatic and supportive. However, possible treatments are being investigated in several clinical trials.

Current therapies

In patients with mucopolysaccharidosis type I, treatment with recombinant human alpha-L-iduronidase reduces lysosomal storage in the liver and ameliorates some clinical manifestations of the disease. [47]

In patients with mucopolysaccharidosis type I, laronidase significantly improves respiratory function and physical capacity, reduces GAG storage, and has a favorable safety profile.

A Hurler syndrome fibroblast cell line heterozygous for the IDUA gene that encodes alpha-L-iduronidase stop mutations Q70X or W402X shows a significant increase in alpha-L-iduronidase activity when cultured in the presence of gentamicin, resulting in the restoration of 2.8% of the normal alpha-L-iduronidase activity.

Allogeneic bone marrow transplantation (BMT) is the only long-lasting treatment that ameliorates or halts the aggressive course of the disease. Pulmonary hemorrhage is an unusual complication of BMT. [48]

Allogeneic hematopoietic SCT, used in severe forms of the disease, markedly prolongs survival, alleviates ventricular hypertrophy, and preserves cardiac function, but cardiac valves continue to thicken and valvular insufficiency progresses. [49]

Cell therapy with human amniotic epithelial cells was developed as an alternative method for enzyme replacement therapy in congenital lysosomal storage disorders, but only limited therapeutic efficacy has been reported. Some studies suggest that the transplantation of human amniotic epithelial cells transduced with adenoviral vectors can be used for the treatment of congenital lysosomal storage disorders. The multiple positive effects include reconstruction of the CNS.

Neonatal screening of these diseases should be mandatory to vastly improve outcomes. Plans are being implemented to use dried blood spots on filter paper, as is commonly performed for many other genetic diseases. Many new therapies are being adopted, which should enhance positivity and acceptance of treatment by hematopoietic SCT.

Many children who undergo SCT have deterioration in hearing following SCT. A high-risk group of children can be delineated who may benefit from more intensive audiologic monitoring following SCT.

For Maroteaux-Lamy syndrome, BMT is the only definitive form of enzyme replacement therapy available. Umbilical cord blood transplantation has also been reported as a treatment of this syndrome.

Yasuda et al report a case report with long-term observation after hematopoietic stem cells transplantation (HSCT) in a patient with mucopolysaccharidosis type I (Hurler syndrome). HSCT at an early stage of mucopolysaccharidosis type I (Hurler syndrome) provides a marked positive impact on clinical central nervous system and skeletal manifestations, bone pathology, and GAG levels. Thus, HSCT should be a primary standard care of mucopolysaccharidosis type I (Hurler syndrome) at an early stage. [50]

Therapy with glucocorticoids, high doses of vitamin A, thyroid hormone, lidase, and growth hormone has been attempted. Glucocorticoids and a corticotropin have been used to block the synthesis of acid mucopolysaccharides. High doses of vitamin A have been used in an effort to increase the urinary excretion of mucopolysaccharides; however, the amount excreted and the clinical response have varied. Lidase is a hyaluronidase that digests mucopolysaccharides. Thyroid hormone substitution is used in patients with hypothyroidism. Some patients with mucopolysaccharidosis are shown to have growth hormone deficiency, and in these cases, growth hormone therapy may be beneficial. Symptomatic anticonvulsive therapy is indicated when epilepsy is present. The prognosis is better and therapy is more successful when treatment is started early.

Treatment with recombinant human N -acetylgalactosamine 4-sulfatase (rhASB) is another possibility in mucopolysaccharidosis type VI. rhASB treatment reportedly was well-tolerated, and reduced lysosomal storage is evidenced by a dose-dependent reduction in urinary GAG. [51]

Flavonoids, as compounds related to genistein (an inhibitor of glycosaminoglycans [GAG] synthesis), are natural candidates for drugs that could be used to manage the neurological symptoms of mucopolysaccharidosis.

Kloska et al have tested the effects of 4 different flavonoids in assays for GAG synthesis, lysosomal structures, and phosphorylation of epidermal growth factor receptor. Skin fibroblasts obtained from mucopolysaccharidosis type IIIA and mucopolysaccharidosis type IIIB patients were used in all experiments, and a human dermal fibroblasts adult cell line was used as a healthy control line. Their studies revealed that apigenin (a flavone), daidzein (an isoflavone), kaempferol (a flavonol), and naringenin (a flavanone) caused a decrease in the efficiency of GAG synthesis, although only daidzein and kaempferol caused statistically significant differences relative to untreated cells. Nevertheless, in the presence of all these compounds, lysosomal storage in mucopolysaccharidosis type IIIA fibroblasts was significantly decreased. Flavonoids can be considered as potential drugs. Obviously, further tests, including those with animal models, are necessary to prove their safety for organisms. [52]

Treatments in clinical trials

No cure exists for mucopolysaccharidosis; treatment is symptomatic and supportive. However, possible treatments are being investigated in several clinical trials.

Mucopolysaccharidosis type I

Laronidase (Aldurazyme) is an enzyme replacement therapy for patients with mucopolysaccharidosis type I, a progressive, debilitating, and fatal genetic disease for which specific drug treatments currently are available. In a press release in September 2002, BioMarin and Genzyme included clinical data from the 6-month, placebo-controlled, phase 3 trial of laronidase; 6 months of data from the ongoing open-label, phase 3 extension study; and 3 years of data from the phase 1 trial and extension study. Laronidase was approved in the United States in April 2003.

The study of a double-blinded, placebo-controlled trial reported by Muenzer et al supports the use of weekly infusions of idursulfase in the treatment of mucopolysaccharidosis type II. [53] Idursulfase was generally well tolerated, but infusion reactions did occur. Idursulfase antibodies were detected in 46.9% of patients. [54, 55]

Mucopolysaccharidosis type II

In a press release from October 2002, Transkaryotic Therapies Inc (TKT) reported results from a phase 1/2 study evaluating its investigational enzyme replacement therapy with I2S as a treatment of Hunter syndrome. The randomized, double-blinded, placebo-controlled study evaluated the safety of I2S (human I2S produced by genetic engineering technology) and its clinical activity in 12 patients with Hunter syndrome. Three doses were studied (0.15 mg/kg, 0.5 mg/kg, and 1.5 mg/kg), and within each dose group, 3 patients were randomized to receive I2S and 1 was to receive placebo by a 60-min intravenous infusion biweekly for 6 months.

In the trial, I2S administration was generally well tolerated, and in the phase 1/2 trials, evidence of clinical activity with Hunter syndrome, including reduced cardiac mass, stabilized pulmonary function, and reduced GAG levels, was demonstrated. The most common adverse effects from I2S treatment were hives, chills, fever, and facial flushing. Only 1 of the 9 patients who were treated developed antibody to I2S.

Mucopolysaccharidosis type IVA

Elosulfase alfa (Vimizim; BioMarin Pharmaceutical, Inc.) was approved by the FDA in February 2014 for patients with Morquio A syndrome (mucopolysaccharidosis Type IVA [MPS IVA]). Approval was supported by a 24-week, randomized, clinical trial involving 176 patients. The primary endpoint of the trial, change in 6-minute walk distance at 24 weeks, was statistically significant in patients who received weekly elosulfase alfa 2 mg/kg IV infusions. The walking distance improved in the elosulfase alfa group with a mean increase of 22.5 meters over placebo. Walking ability was sustained in patients who continued weekly elosulfase alfa for an additional 48 weeks. [56]

Mucopolysaccharidosis type VI

The clinical trial of rhASB (Aryplase), an investigational enzyme replacement therapy for mucopolysaccharidosis type VI, continues to evaluate the efficacy, safety, and pharmacokinetics of weekly intravenous infusions of 1 mg/kg of rhASB in 10 patients with mucopolysaccharidosis type VI. In June 2002, BioMarin Pharmaceutical announced findings from the 24-week open-label extension of the phase 1 clinical trial; the enzyme was well tolerated by all patients, and reduced urinary excretion of GAG was maintained in both treatment arms. [57]

It was confirmed in the phase 3 of the randomized, double-blinded, placebo-controlled, multicenter, multinational study that rhASB significantly improves endurance, reduces urinary GAG excretion, and has an acceptable safety profile. After 24 weeks, patients receiving rhASB walked on average 92 meter more in the 12-minute walk test and climbed 5.7 stairs per minute more in a 3-minute stair climb test than patients receiving placebo. Urinary GAG declined by -227 ±18 mcg/mg more with rhASB than placebo. Patients exposed to the drug experienced positive clinical benefits despite the presence of antibody to the protein.

Mucopolysaccharidosis type VII

Emil Kakkis, MD, PhD, and William Sly, MD, have received a grant to develop enzyme replacement for mucopolysaccharidosis type VII. They are making steady progress with BioMarin Pharmaceutical, but no timeline for human clinical trials is projected.

Updated clinical trial data and recruiting

For updated clinical trial results and for trials that are completed and recruiting see ClinicalTrials.gov.

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Surgical Care

Treatment is symptomatic. Orthopedic surgeries may be required for mucopolysaccharidosis types I, II, IV, VI, and VII to correct the deformities and increase patient quality of life. Tonsillectomy and adenoidectomy may help improve the patients’ respiratory status. Other complications can be managed with myringotomy, heart-valve replacement, and decompression of the cervical spinal cord. [58]

Surgical procedures may include corneal transplantation and correction of nerve entrapments in the hands.

Correction of the contractures and osteal deformities may be performed. For patients with mucopolysaccharidosis type IV, cervical myelopathy should be prevented by surgery of the cervical spine.

Occipital to C3 decompression and fusion with autogenous rib grafts may be performed. The youngest patient who underwent this successful posterior cervical arthrodesis was 17-month-old boy with Sly syndrome.

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Consultations

Genetic counseling is of great importance to ensure prenatal diagnosis.

Mucopolysaccharidoses create a special challenge for the otolaryngologist. With the rare types of mucopolysaccharidosis type IV and mucopolysaccharidosis type I-S, a skilled practitioner is required to manage airway complications. The erratic deposits of mucopolysaccharides throughout the trachea should be taken into account when a decision is made to stent the airway. Proper management requires an airway that is custom made to meet the patient's needs.

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Complications

Mucopolysaccharidosis type I (Hurler syndrome)

Complications include heart valve damage from thickening due to coronary artery disease, severe mental retardation, umbilical and inguinal hernia, deafness, premature death, and constipation alternating with diarrhea.

Mucopolysaccharidosis type II (Hunter syndrome)

Complications include airway obstruction in the late-onset form, progressive mental deterioration in the early-onset form (severe form), progressive loss of ability to perform daily living activities in the early-onset form (severe form), progressive hearing loss in both the mild and severe forms, progressive joint stiffness leading to contractures of the joints in the early-onset form (severe form), and carpal tunnel syndrome. Of the complications observed after tracheotomy, infrastomal tracheal stenosis and stomal narrowing are frequent. Intubation in children with mucopolysaccharidosis type II is more difficult (20 times more) than in other children of a similar age or weight. [59]

Mucopolysaccharidosis type III (Sanfilippo syndrome)

Complications include blindness, seizures, mental retardation, progressive neurologic disease leading to patients becoming wheelchair bound, and the inability to care for oneself.

Mucopolysaccharidosis type IV (Morquio syndrome)

Complications include heart failure, difficulty with vision, walking problems due to abnormal curvature of the spine, and breathing problems. Abnormal neck bones can cause spinal cord damage that can result in severe disease, including paralysis, if not noticed early. Spinal fusion can prevent this complication.

Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome)

Complications include hearing loss, vision loss, carpal tunnel syndrome, and valvular heart disease.

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Prevention

Genetic counseling may be performed.

Prenatal diagnosis is possible. Amniocentesis can be performed; cells in the amniotic fluid are cultured, and the alpha-L-iduronidase activity in the cells is determined.

As determined by Altarescu et al, preimplantation genetic diagnosis (PGD) is a reliable method to prevent pregnancies of children affected with Hunter syndrome. In addition, they report the first ever derivation of a Hunter syndrome (46,XX) human stem cell line from embryos carrying the iduronate-2-sulfatase and oculocutaneous albinism type 2 mutations. PGD is a technique that precludes the need for pregnancy termination in cases of an affected fetus, by virtue of analysis of the 6- to 8-cell stage embryos (obtained by in vitro fertilization) and transfer of only unaffected embryos. [60]

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Long-Term Monitoring

All patients with mucopolysaccharidosis type I should receive a comprehensive baseline evaluation, including neurologic, ophthalmologic, auditory, cardiac, respiratory, gastrointestinal, and musculoskeletal assessments. Additionally, all patients should be monitored every 6-12 months with individualized specialty assessments, to monitor disease progression and effects of intervention. Patients are best treated by a multidisciplinary team. Treatments consist of palliative/supportive care, hematopoietic stem cell transplantation, and enzyme replacement therapy. The patient's age (>2 y or 2 y), predicted phenotype, and developmental quotient help define the risk-to-benefit profile for hematopoietic SCT transplantation (higher risk but can preserve CNS function) versus enzyme replacement therapy (low risk but cannot cross the blood-brain barrier).

International expert panels recommend the evaluation of ocular features at least every 12 months for patients with mucopolysaccharidosis type I and mucopolysaccharidosis type VI. [30]

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