Genetics of Mucopolysaccharidosis Type IV Workup
- Author: Nancy E Braverman, MS, MD; Chief Editor: Maria Descartes, MD more...
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.
See the list below:
- 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)
- 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 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)
- Standing pelvis view with visualization of the femoral heads articulating with the acetabulum (see image below)
- Preferably standing AP views of the lower extremities, including the entire femur, articulation with tibia (knees for genu valgus), and ankles (see image below)
- 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 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.
- 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.
See the list below:
- 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.
See the list below:
- 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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|Neuro-degeneration||Somatic Features*||Corneal Clouding||Bone / Joint Abnormality||Mucopoly-saccharide Stored|
|IH||Hurler||α -iduronidase||+++||+++||++||++||Dermatan sulfate (DS), heparan sulfate (HS)|
|IH/S||Hurler-Scheie||α -iduronidase||—||++||++||++||DS, HS|
|IS||Scheie||α -iduronidase||—||+||+||+||DS, HS|
|II||Hunter||Iduronidase sulfatase||++||++||—||++||DS, HS|
|III †||Sanfilippo A||Heparan sulfatase||+++||+||—||+||HS|
|Sanfilippo B||N -acetylgluco-saminidase||+++||+||—||+||HS|
|Sanfilippo C||Acetyl CoA glucosamine acetyltransferase||+++||+||—||+||HS|
|Sanfilippo D||N -acetylglucosamine-6-sulfatase||+++||+||—||+||HS|
|IV||Morquio A||Galactosamine-6-sulfatase||—||+||+ / —||+ / ++ / +++||KS, chondroitin sulfate (CS)|
|Morquio B||β -galactosidase||—||+||+ / —||+ / ++ / +++||KS, CS|
|VII||Sly ‡||β -glucuronidase||—||++||++||++||DS, HS, CS|
|IX||Hyaluronidase 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.
|MPS Type||Disease Name||Enzyme Deficiency||ERT||Company||Clinical Use|
|IH/S||Hurler-Scheie||α -iduronidase||laronidase||Genzyme||In use|
|IS||Scheie||α -iduronidase||laronidase||Genzyme||In use|
|III ‡||Sanfilippo A||Heparan sulfatase||...||...||...|
|Sanfilippo B||N- acetylglucosaminidase||...||...||...|
|Sanfilippo C||Acetyl CoA glucosamine acetyltransferase||...||...||...|
|Sanfilippo D||N -acetylglucosamine-6-sulfatase||...||...||...|
|IV||Morquio A||N-acetylgalactosamine-6-sulfatase||elosulfase alfa (Vimizim)||BioMarin||In use|
|Morquio B||β -galactosidase||...||...||...|
|VI||Maroteaux-Lamy||N -acetylhexosamine-4-sulfatase||galsulfase (Naglazyme)||BioMarin||In use|
|VII||Sly §||β -glucuronidase||...||...||...|
|IX||Hyaluronidase Deficiency || |||Hyaluronidase||...||...||...|
|GSDII||Pompe||Acid α -glucosidase||alglucosidase (Myozyme)||Genzyme||In use|
|Note. This table represents the status of enzyme replacement therapy as of February 2014. Progress occurs on a daily basis; please investigate further for the most up to date information.|