Genetics of Mucopolysaccharidosis Type IV Workup

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

Laboratory Studies

The following tests are indicated in patients with Morquio syndrome (mucopolysaccharidosis type IV):

  • Urine spot tests are readily available to screen for mucopolysaccharides.
    • These tests are associated with false-positive and false-negative results; testing more than one urine sample is recommended.
    • In Morquio syndrome (mucopolysaccharidosis type IV), mildly affected patients do not always excrete keratan sulfate (KS) fragments.
  • Semiquantification of urinary glycosaminoglycans (GAGs) can be obtained by spectrophotometric assays with dimethylmethylene blue. Heparan sulfate (HS), KS, and dermatan sulfate (DS) can be distinguished by electrophoretic techniques to narrow the differential among the mucopolysaccharidoses (MPSs).
  • A new enzyme-linked immunoassay (ELISA) technique has been shown to accurately quantify KS in urine and blood in patients with Morquio syndrome type IVA.
  • Clinical suspicion should take precedence over screening test results because of their variability.
  • The diagnosis is confirmed by direct enzymatic assay in leukocytes or fibroblasts.
    • The enzymes deficient in Morquio syndrome (mucopolysaccharidosis type IV) are galactosamine-6-sulfatase (ie, N -acetyl-galactosamine-6-sulfate sulfatase) and β -galactosidase.
    • University hospitals with expertise in metabolic genetics perform these assays on heparinized blood or fibroblasts cultured from a small (2 mm) skin biopsy.
  • For prenatal diagnosis, enzyme activity can be measured in amniocytes or chorionic villi.
  • Determination of the carrier state by enzyme analysis is not always possible because the range of enzyme activity in noncarrier and carrier individuals overlaps.
    • Detection of mutations in the GALNS and GLB1 genes can facilitate carrier testing if the family desires.
    • GeneTests lists several institutions that offer enzymatic and mutation analysis for Morquio syndrome (mucopolysaccharidosis type IV).
    • Obtaining specific instructions from the laboratory performing these assays prior to collecting samples from patients is beneficial.
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Imaging Studies

  • A full skeletal survey should be obtained in a patient thought to have MPS. For Morquio syndrome (mucopolysaccharidosis type IV), the authors recommend the following radiographic studies:
    • Anteroposterior (AP) and lateral views of the skull with visualization of the sella
    • Flexion and extension radiographs of the cervical spine (see image below)Cervical spine, flexion and extension views, in a 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.
    • AP and lateral views of the odontoid
    • AP and lateral views of the chest (see image below)Anteroposterior view of the chest in a child aged 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.
    • Standing AP and lateral views of entire spine (see image below)Lateral view of spine in a child aged 8 years and 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.
    • Standing pelvis view with visualization of the femoral heads articulating with the acetabulum (see image below)Multiple abnormalities are present in the pelvis, 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.
    • Preferably standing AP views of the lower extremities, including the entire femur, articulation with tibia (knees for genu valgus), and ankles (see image below) Bilateral lower extremity views in a patient aged 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.
    • AP views of at least one foot, one hand, forearm, elbow in extension, humerus, and shoulder (see images below)Bilateral hand radiographs in a patient aged 22 yeBilateral 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 mUpper 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.
  • CT scanning or MRI of the brain stem and cervical spine should be performed to evaluate odontoid hypoplasia and cord compression. The authors recommend additional CSF flow studies in flexion and extension in patients older than 5 years.
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Other Tests

  • An ophthalmology examination with slit lamp should be performed at the time of initial evaluation to look for corneal clouding. Other rare abnormalities include lens opacities, retinopathy, optic atrophy, and pseudoexophthalmos.
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Histologic Findings

  • The lysosomes of patients with MPS are engorged with unmetabolized GAG. These appear as vacuoles or inclusion bodies in cells such as lymphocytes, hepatocytes, corneal epithelium, and neurons.
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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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