Genetics of Mucopolysaccharidosis Type IV Treatment & Management

  • Author: Nancy E Braverman, MS, MD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 22, 2012
 

Medical Care

  • Condition specific height and weight curves are now available to follow patients longitudinally with Morquio syndrome (mucopolysaccharidosis type IV). Final height is attained for most males at age 11 years and for females at age 9 years.
  • Only palliative measures are currently available for treatment of patients with Morquio syndrome (mucopolysaccharidosis type IV).
  • Potential strategies for treatment of patients with the other mucopolysaccharidoses (MPSs), which are currently at different levels of development, include enzyme replacement therapy (ERT),[4] gene therapy, and allogenic bone marrow transplantation in which engrafted cells provide the normal enzyme.
  • Currently, ERT is available commercially for MPS type I (Hurler disease), MPS type VI (Maroteaux-Lamy disease), Gaucher disease, Fabry disease, MPS type II (Hunter disease), and Pompe disease. See Table 2.
  • ERT is currently under development for Morquio syndrome type IVA and will be in trial phase in the near future.
  • The historic observation that glycosaminoglycans (GAG) deposition in cultured cells from patients with MPS can be diminished by providing the deficient enzyme in soluble form promoted lysosomal storage disease as a paradigm for treatment with exogenous enzyme.
    • Animal models have facilitated the testing of various therapies, but many technical difficulties remain to be overcome.
    • The refractory response of skeletal abnormalities to enzyme replacement in Hurler and Gaucher disease type 1 is of particular concern in the exploration of therapies for patients with Morquio syndrome (mucopolysaccharidosis type IV).

Table 2. Enzyme Replacement Therapy for the Mucopolysaccharidoses (Open Table in a new window)

MPS TypeDisease NameEnzyme DeficiencyERTCompanyClinical Use
IHurlerα -iduronidaseAldurazymeGenzymeIn use
IH/SHurler-Scheieα -iduronidaseAldurazymeGenzymeIn use
ISScheieα -iduronidaseAldurazymeGenzymeIn use
IIHunterIduronidase sulfataseElapraseShireIn use
III ‡ Sanfilippo AHeparan sulfatase.........
Sanfilippo BN- acetylglucosaminidase.........
Sanfilippo CAcetyl CoA glucosamine acetyltransferase.........
Sanfilippo DN -acetylglucosamine-6-sulfatase.........
IVMorquio AGalactosamine-6-sulfataseUnnamedVivendy BiomarinIn development
Morquio Bβ -galactosidase.........
VIMaroteaux-LamyN -acetylhexosamine-4-sulfataseNaglazymeBiomarinIn use
VIISly § β -glucuronidase.........
IXHyaluronidase Deficiency || |Hyaluronidase.........
GSDIIPompeAcid α -glucosidaseMyozymeGenzymeIn use
Note. This table represents the status of enzyme replacement therapy as of November 2008. Progress occurs on a daily basis; please investigate further for the most up to date information.
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Surgical Care

  • Because all patients with Morquio syndrome (mucopolysaccharidosis type IV) have odontoid hypoplasia that can lead to atlantoaxial subluxation, many physicians recommend cervical spine fusion, especially for an atlantodens interval more than 8 mm or space around the cord less than 14 mm.[5] Some physicians recommend fusion of C1 and C2, whereas others recommend fusion of C1 and C2 and occipital fusion if basilar invagination, inadequate fixation to C1, or occiput-C1 instability is also noted. Patients undergoing cervical fusion wear a halo brace for an extended period after the surgery. Ideally, the surgery should be performed before signs and symptoms of cervical myelopathy occur. However, because of the high risk of this procedure in patients with Morquio syndrome (mucopolysaccharidosis type IV), some elect not to have this surgery.
  • Patients with Morquio syndrome (mucopolysaccharidosis type IV) can develop an extradural soft tissue GAG accumulation anterior to the cord at C1, which can cause myelopathy.
  • One study stressed the importance of monitoring craniovertebral posture and mandibular growth after cervical fusion in a patient with Morquio syndrome (mucopolysaccharidosis type IV). Excessive mandibular growth occurred after the fusion procedure, thought to be secondary to the new postoperative position of the head, neck, and tongue.
  • Other potential operations for patients with Morquio syndrome (mucopolysaccharidosis type IV) include femoral osteotomies and corrective knee surgery for genu valgus deformity. Total joint replacement of hips and/or knees may be necessary. The early use of a back brace may delay or prevent surgical intervention for scoliosis.
  • Corneal grafting for progressive corneal haziness has been reported with variable recurrence success.
  • The anesthesiologist for any surgery performed on a patient with Morquio syndrome (mucopolysaccharidosis type IV) must be prepared to manage a difficult airway.
    • A preoperative evaluation should be pursued, especially if evidence of cardiac dysfunction, obstructive apnea, or pulmonary insufficiency is present.
    • The authors recommend obtaining preoperative echocardiography, pulmonary function testing, and sleep studies.
    • Elective surgery should be avoided during temporary respiratory compromise (eg, upper respiratory infection [URI], pneumonia).
    • Alternatives to general anesthesia should be considered. For example, the use of spinal anesthesia has been reported in patients with Morquio syndrome (mucopolysaccharidosis type IV) who are undergoing extensive orthopedic procedures.[6] However, spinal anesthesia can be technically compromised by abnormal vertebrae in these patients, and emergent intubation may still be required.
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Consultations

The multisystem involvement of MPS necessitates a comprehensive care plan.

  • Patients with Morquio syndrome (mucopolysaccharidosis type IV) should be evaluated regularly by a geneticist, an ophthalmologist, an orthopedist, and a cardiologist.
  • Other considerations are consultations with an audiologist and a dentist.
  • Genetic counseling should be provided to patients with newly diagnosed MPS and their families. Because this is an autosomal recessive disorder, a 25% risk for the parents to have another child with Morquio syndrome (mucopolysaccharidosis type IV) is noted in each pregnancy.
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Diet

  • No specific dietary restrictions are indicated for patients with Morquio syndrome (mucopolysaccharidosis type IV).
  • On a practical level, these patients should avoid excess body weight to minimize pulmonary compromise caused by the skeletal deformities.
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Activity

  • A person with Morquio syndrome (mucopolysaccharidosis type IV) can participate in activities as tolerated with a few important restrictions.
  • Contact sports could damage the cervical spine and should be avoided.
  • Repetitive motions at work or with sports could strain abnormal joints and should also be avoided.
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Contributor Information and Disclosures
Author

Nancy E Braverman, MS, MD  Associate Professor, Department of Human Genetics, McGill University

Nancy E Braverman, MS, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Human Genetics, Society for Inherited Metabolic Disorders, and Society for the Study of Inborn Errors of Metabolism

Disclosure: Nothing to disclose.

Coauthor(s)

Shunji Tomatsu, MD, PhD  Professor, Department of Pediatrics, Saint Louis University School of Medicine

Shunji Tomatsu, MD, PhD is a member of the following medical societies: National MPS Society, Japan

Disclosure: Nothing to disclose.

Michael C Ain, MD  Associate Professor, Departments of Neurosurgery and General Surgery, Division of Pediatric Orthopaedic Surgery, Johns Hopkins University School of Medicine

Michael C Ain, MD is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American Orthopaedic Association, Pediatric Orthopaedic Society of North America, and Scoliosis Research Society

Disclosure: Nothing to disclose.

Julie Hoover-Fong, MD, PhD, FACMG  Assistant Professor, Director, Greenberg Center for Skeletal Dysplasias, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University

Julie Hoover-Fong, MD, PhD, FACMG is a member of the following medical societies: American College of Medical Genetics, American Society of Human Genetics, and International Skeletal Dysplasia Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Karl S Roth, MD  Professor and Chair, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Margaret M McGovern, MD, PhD  Professor and Chair of Pediatrics, Stony Brook University, New York

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics

Disclosure: Genzyme Grant/research funds PI

Daniel Rauch, MD, FAAP  Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine

Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine

Disclosure: Baxter Honoraria Consulting

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Julie Hoover-Fong, MD and Michael C Ain, MD,to the original writing and development of this article.

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Lateral view of spine in a child aged 8 years and 7 months. This radiograph shows advanced platyspondyly, irregularity, and anterior beaking of vertebral bodies characteristic of dysostosis multiplex. Note also the gibbus deformity and lordosis, which are characteristic of Morquio syndrome.
Cervical spine, flexion and extension views, in a child aged 5 years and 11 months. These flexion and extension images depict anterior and posterior subluxation, respectively, of the atlas secondary to odontoid hypoplasia.
Bilateral lower extremity views in a patient aged 22 years and 6 months. Metaphyseal irregularities and the characteristic genu valgus deformity are easily observed in this image.
Bilateral hand radiographs in a patient aged 22 years and 6 months. Note the tapering of the proximal portion of metacarpals 2 through 5 and small irregular carpal bones. The epiphyseal involvement characteristic of Morquio syndrome is exemplified by the tapered irregular distal radius and ulna. Overall, the bones are osteopenic with cortical thinning.
Upper extremities in a child aged 6 years and 11 months. Note the irregular epiphyses and widened metaphyses. Cortical thinning and mild widening of the diaphysis of the humerus are visible.
Multiple abnormalities are present in the pelvis, including dysplastic femoral heads and oblique acetabular roof with coxa valgus deformity. Flared iliac wings usually observed in Morquio syndrome are not well represented in this radiograph.
Anteroposterior view of the chest in a child aged 8 years and 4 months with Morquio syndrome. To reference the relatively small size of this chest, this patient's vital capacity was 500 cc, but the expected value based on height and weight was 1400 cc. Widened metaphyses and irregular epiphyses of the humeri and generalized platyspondyly are present. Oar-shaped ribs (widening ribs anteriorly and narrowing at the vertebrae) are easily observed and are another key characteristic of dysostosis multiplex.
Defects in keratan sulfate (KS) degradation resulting in Morquio syndrome.
The individual on the front of the scooter is 19 years old and has Morquio syndrome. Her friend on the back is an average-stature 10 year old without Morquio syndrome. On the driver, note the enlargement at the knees and the wrist deformity. Also, note the successful adaptation of the scooter to ambulate.
Note the short trunk and protuberant rib structure in this child with Morquio syndrome. More importantly, notice that Morquio syndrome is not preventing this child from being active and fishing.
Table 1. Clinical and Biochemical Features Distinguishing the Mucopolysaccharidoses and Morquio Syndrome (Mucopolysaccharidosis Type IV)
MPS TypeEponymDeficient



Enzyme



Neuro-degenerationSomatic Features*Corneal CloudingBone / Joint AbnormalityMucopoly-saccharide Stored
IHHurlerα -iduronidase++++++++++Dermatan sulfate (DS), heparan sulfate (HS)
IH/SHurler-Scheieα -iduronidase—++++++DS, HS
ISScheieα -iduronidase—+++DS, HS
IIHunterIduronidase sulfatase++++—++DS, HS
III † Sanfilippo AHeparan sulfatase++++—+HS
Sanfilippo BN -acetylgluco-saminidase++++—+HS
Sanfilippo CAcetyl CoA glucosamine acetyltransferase++++—+HS
Sanfilippo DN -acetylglucosamine-6-sulfatase++++—+HS
IVMorquio AGalactosamine-6-sulfatase—++ / —+ / ++ / +++KS, chondroitin sulfate (CS)
Morquio Bβ -galactosidase—++ / —+ / ++ / +++KS, CS
VNonexistent
VIMaroteaux-LamyN -acetylhexosamine-4-sulfatase—++++DS
VIISly ‡ β -glucuronidase—++++++DS, HS, CS
IXHyaluronidase deficiency § Hyaluronidase———+Hyaluron
*Somatic features include organomegaly and facial coarsening.



† Eye findings may include cherry red spots.



‡ Severity widely varies; no neurologic degeneration is noted, but mental retardation is possible.



§ Only one patient has been described whose major features were periarticular soft tissue masses.



Table 2. Enzyme Replacement Therapy for the Mucopolysaccharidoses
MPS TypeDisease NameEnzyme DeficiencyERTCompanyClinical Use
IHurlerα -iduronidaseAldurazymeGenzymeIn use
IH/SHurler-Scheieα -iduronidaseAldurazymeGenzymeIn use
ISScheieα -iduronidaseAldurazymeGenzymeIn use
IIHunterIduronidase sulfataseElapraseShireIn use
III ‡ Sanfilippo AHeparan sulfatase.........
Sanfilippo BN- acetylglucosaminidase.........
Sanfilippo CAcetyl CoA glucosamine acetyltransferase.........
Sanfilippo DN -acetylglucosamine-6-sulfatase.........
IVMorquio AGalactosamine-6-sulfataseUnnamedVivendy BiomarinIn development
Morquio Bβ -galactosidase.........
VIMaroteaux-LamyN -acetylhexosamine-4-sulfataseNaglazymeBiomarinIn use
VIISly § β -glucuronidase.........
IXHyaluronidase Deficiency || |Hyaluronidase.........
GSDIIPompeAcid α -glucosidaseMyozymeGenzymeIn use
Note. This table represents the status of enzyme replacement therapy as of November 2008. Progress occurs on a daily basis; please investigate further for the most up to date information.
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