Mucopolysaccharidoses Types I-VII Workup

Updated: May 13, 2022
  • Author: Janette Baloghova, MD, PhD; Chief Editor: Dirk M Elston, MD  more...
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Laboratory Studies

The diagnosis is based on the clinical picture, radiographic findings, and laboratory results.

The diagnosis of mucopolysaccharidosis can be achieved by nonenzymatic screening methods, including the 2-dimensional electrophoresis method and the dimethylmethylene blue method. The 2-dimensional electrophoresis method reveals separation of urinary GAGs, and the dimethylmethylene blue method can be used to estimate the concentration of GAG in urine. Both methods are specific, sensitive, and easy to perform for mucopolysaccharidosis screening. Quantitation of urinary GAGs alone is not diagnostic of mucopolysaccharidosis; it should be coupled with qualitative analysis and enzyme estimations for differential/definitive diagnosis. Quantitation of isolated urinary GAGs can be performed using the acid Alcian blue complex formation method, and qualitative urinary GAG analysis can be performed by multisolvent sequential thin layer chromatography. [35]  Metachromatic granulations can be detected in the leukocytes in blood or bone marrow cells (Adler-Reilly granules containing GAGs).

Measurement of iduronate-2-sulfatase (I2S) protein concentration with a 2-step, time-delayed, dissociation-enhanced lanthanide fluorescence immunoassay and enzyme activity with the fluorogenic substrate 4-methylumbelliferyl sulfate from the dried blood spots and plasma samples enables the detection of mucopolysaccharidosis type II. [36]

The release of GAG into the urine is used as a biomarker of disease, in some cases reflecting disease severity, and in all cases reflecting therapeutic responsiveness. Using RNA studies in 4 Italian patients undergoing enzyme replacement therapy, Di Natale et al observed that tumor necrosis factor-alpha might be a biomarker for mucopolysaccharidosis type VI that is responsive to therapy. In addition to its role as a potential biomarker, tumor necrosis factor-alpha expression could provide insights into the possible pathophysiological mechanisms underlying the mucopolysaccharidoses. [37]

A new alpha-L-iduronidase substrate was synthesized to be used to assay the enzyme by use of tandem mass spectrometry together with an internal standard or by fluorometry. The assay uses a dried blood spot on a newborn screening card as the enzyme source. Tandem mass spectrometry assay has the potential to be adopted for newborn screening of mucopolysaccharidosis type I. [38]

The serum levels of heparin cofactor II–thrombin complex is a reliable biomarker of the mucopolysaccharidoses. Untreated patients have serum levels that range from 3- to 112-fold higher than control values. In a series of patients with varying severity of mucopolysaccharidosis type I, the serum complex concentration was reflective of disease severity. [39]

Study of Dung et al provided evidence of extensive allelic heterogeneity of mucopolysaccharidosis type IVA. The urine GAGs are within normal limits in 10-20% of patients. If mucopolysaccharidosis type IVA is clinically suspected, the assay for keratan sulfate in blood and urine is preferable, followed by GALNS (N -acetylgalactosamine-6-sulfate sulfatase) enzyme assay in peripheral leukocytes or fibroblasts. [40]


Imaging Studies


In mucopolysaccharidosis type II, generalized symmetric damage of the epiphysis is noted. They are flattened and augmented. The metadiaphyseal parts of the tubular bones are shortened and thickened. Valgus deformity of the proximal parts of the femur and deformation of the plate bones are observed. Thickening of the ribs and shortening of the intercostal distance are noted. Platyspondylia of the columna vertebrarum with angle kyphosis in the lumbar and thoracic regions is evident. No changes are evident in the intervertebral spatia. The basis cranii is short; the sella turcica is flattened and prolonged. Blockage of the pneumatization and asymmetric osteogenesis are present.

In mucopolysaccharidosis type IV, epiphyseal growth is disturbed. For the columna vertebrarum, platybrachyspondylia is characteristic. No disturbances are present in the intervertebral disks. In the thorax, the anteroposterior distance is augmented, while the intercostal distance is decreased.

Characteristic radiological findings of mucopolysaccharidosis VI, other mucopolysaccharidoses, mucolipidoses, and other storage diseases are termed dysostosis multiplex. Typical radiological findings include thickened, short metacarpal bones with proximal pointing and thin cortices; carpal bones that are irregular and hypoplastic and tarsal bones that have irregular contours; a dysplastic femoral head; severe hip dysplasia; abnormal development of vertebral bodies of the spine; paddle-shaped widened ribs and short, thick irregular clavicles, hypoplastic distal ulna and radius; thickened diploic space; and abnormally shaped J-shaped sella in the cranium. Slowly progressing mucopolysaccharidosis type VI patients may not demonstrate all the above characteristics of dysostosis multiplex. [23]

Radiographic features of oral and maxillofacial manifestations in patients with mucopolysaccharidoses can involve taurodontism, enamel hypoplasia, enlarged cystlike dental crypts, microdont third molars and supernumerary teeth (forth molars), enlargement of bone marrow and thinning of cortical bone related to the accumulation of mucopolysaccharides in the bone tissues of the jaws, and irregularities of the condyle, characterized as excessive wear and erosions in the surface of the condyle and teeth impaction. [41]

Magnetic resonance imaging (MRI)

MRI is the primary imaging technique to detect CNS alterations. The presence of white matter alterations is significantly correlated with mental retardation. Other possible CNS alterations are perivascular, subarachnoid, and ventricular space enlargement and abnormalities of the basal ganglia, the corpus callosum, and the atlantoaxial joint. [42, 43]

Brain atrophy usually develops earlier in mucopolysaccharidosis types I, II, III, and VII, becoming visible during the first few years of life. Patients with mucopolysaccharidosis types IV and VI typically have normal intelligence and do not show signs of atrophy until the second decade of life. The atrophy of the brain is seen as widened subarachnoid spaces and enlargement of the cortical sulci. The MRI evaluation of these findings is a useful marker of axonal loss. [44]

Magnetic resonance spectroscopy (MRS)

MRS is a noninvasive imaging technique able to provide information about tissue molecular structures. Some studies have suggested a contribution of MRS to mucopolysaccharidoses assessment (a reduction of the white matter N -acetylaspartate/creatine [NAA/Cr] ratio in mucopolysaccharidosis types IVA and II proportional to cognitive indices and to disease progression, an elevated myo-inositol/creatine [mIns/Cr] ratio in patients with cognitive impairment, a reduction in mucopolysaccharides in white matter without lesions after bone marrow transplantation, and correlation between mucopolysaccharide accumulation and neuronal damage). The future will show the significance of MRS in the evaluation of neurological involvement in mucopolysaccharidoses. [44]

CT scanning

A thickened, retracted tympanic membrane and increased attenuation of the tympanic cavity and mastoid cells can be observed on multidetector computed tomography (MDCT) images. Multiplanar reconstruction of a MDCT scan, usually performed for the evaluation of the atlantoaxial instability, may be an important tool to assess the status of the whole airway passage. [44]


Other Tests

Carrier status can be determined by performing enzymatic assays in high-risk individuals.

Prenatal diagnosis for most of these disorders is available to high-risk mothers, such as mothers of an affected offspring, who face a 25% chance of having another affected offspring in a subsequent pregnancy.

In mucopolysaccharidosis type III, flash visual evoked potentials and brainstem auditory evoked potentials are almost always normal; electroencephalography findings are often abnormal early in the disease. [45]

Patients who present with progressive noninflammatory joint involvement in the first decade of life, particularly with stiffness of the fingers and difficulty using the hands, should be screened for metabolic diseases, including mucopolysaccharidosis type I. [46] Mucopolysaccharidosis type I should be considered if patients with arthropathy lack the typical characteristics of inflammatory arthropathy.

Screening for vitreous abnormalities and maculopathy may be important in diagnosing, treating, and explaining visual loss in persons with Hunter syndrome. [47]


Histologic Findings

In all types of mucopolysaccharidosis, normal or slightly thickened skin shows metachromatic granules within the fibroblasts by using Giemsa or toluidine blue staining. These metachromatic granules are occasionally evident within keratinocytes and eccrine structures. The characteristic cutaneous pebbling in Hunter syndrome shows these granules within the dermal fibroblasts and extracellular metachromatic material between the collagen bundles. In all types of mucopolysaccharidosis, the cytoplasm of circulating lymphocytes also demonstrates these granules. Patients with Morquio syndrome show reduced activity of N -acetyl-galactosamine-6-sulfatase on fibroblast culture obtained from a skin biopsy sample.