Case 2 -
Mucopolysaccharidosis Type I (MPS I, Hurler Syndrome)
Carole A. Vogler
Cardinal Glennon Children's Hospital
St. Louis, MO
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A ten-month-old African-American boy presented with rhinorrhea and fever. The child was the product
of a normal term pregnancy born to a 22-year-old G2 P2 mother. He had a history of bilateral inguinal
hernias repaired at age two months. Family history was negative for developmental disease. Three
half-siblings were all in good health. Physical examination showed a weight > 50th
percentile, height > 10th percentile, head circumference > 95th percentile
for his age. He had an abnormal facies with frontal bossing, a flat nasal bridge, and coarse features,
and "spade-like" hands with short "stubby" fingers. He had no gibbus. A 1.5 cm umbilical hernia and
hepatosplenomegaly were present; the liver was 6 cm below the right coastal margin and the spleen was 3
cm below the left coastal margin. He had bilateral corneal clouding. A biopsy was performed.
Case 2 - Figure 1 - The conjunctival connective tissue contains numerous fibroblasts distended by what appear by light microscopy to be empty vacuoles. This extensive cytoplasmic vacolization is very suggestive of a lysosomal storage disease. (Toluidine blue)
Case 2 - Figure 2 - By electron microscopy, the vacuoles distending the fibroblasts in the conjunctival stroma are surrounded by a single membrane and contain fine fibrillogranular storage material and occasional electron dense granules. This type of storage material is nonspecific but very characteristic of the mucopolysaccharidoses. It can also be seen in other lysosomal storage diseases, including mucolipidoses, mannosidosis, and sialadosis. (Uranyl acetate-lead citrate)
The fibrillogranular and clear storage distending lysosomes in fibroblasts, endothelial and perineural
cells in the conjunctival biopsy were diagnostic of a lysosomal storage disease (LSD). The findings were
consistent with the clinical diagnosis of mucopolysaccharidosis and MPS I was subsequently confirmed by
documenting deficient leukocyte α-L-iduronidase. Other diagnostic considerations based on the
morphology of the stored material included mucolipidoses, mannosidosis, sialadosis, glutamyl
ribose-5-phosphate storage disease and GM1 gangliosidosis.
Final Diagnosis: Mucopolysaccharidosis Type I (MPS I, Hurler Syndrome)
LSD affect 1/5,000 children and are a heterogeneous group of almost 50 inherited disorders. Most LSD
are the result of a defect in a gene that codes for a specific lysosomal acid hydrolase but defects in a
enzyme coactivator, membrane transporter, targeting mechanism for protein localization to the lysosome or
intracellular vesicular trafficking can also cause LSD
. The enzyme deficiency blocks a catabolic
pathway which leads to progressive accumulation of undegraded substrate macromolecules leading to
cellular and organ dysfunction. Which tissue is affected and at what age symptoms develop depends on the
importance of the degradative pathway in a given tissue. LSD patients have a broad spectrum of
phenotypes; most have progressive neurological degeneration overlaying a variety of musculoskeletal and
visceral abnormalities. Clinical findings that warrant investigation for LSD include nonimmune fetal
hydrops, progressive organomegaly, skeletal abnormalities, joint stiffness, coarse facial features,
progressive dementia or loss of developmental skills and unexplained neuropathic extremity or bone pain
. Patients with MPS, due to deficiency of an enzyme needed for normal catabolism of
glycosaminoglycans, as in this patient, present with progressive hepatosplenomegaly, bone and joint
abnormalities termed dysostosis multiplex, coarse facial features, corneal clouding and developmental
In many patients with LSD, biochemical analysis of cultured fibroblasts, leukocytes or plasma provides
a diagnosis . Tissue biopsy with ultrastructural evaluation can also be useful. Many metabolic
diseases, including LSD, have well characterized ultrastructural alterations in the rectal mucosa, skin,
conjunctiva and peripheral blood leukocytes providing criteria for diagnosis . Cultured fibroblasts
can have artifacts of culture that mimic lysosomal storage  and are not as useful of morphological
evaluation as tissue samples. In some patients with morphological evidence of LSD, a specific disorder
is suggested by the character of the stored material. In others, a differential diagnosis is indicated
by the finding of accumulation of fibrillogranular lysosomal material, as in this case. EM has
particular value in those disorders with incompletely characterized biochemical defects .
Early diagnosis is becoming more important for patients with LSD as effective disease-specific therapy
becomes a reality for these disorders. Patients are ideally diagnosed before serious mental or physical
impairments are present . A newborn screening program that measures levels of the
lysosomal-associated membrane protein, LAMP-1, and saposins, which are elevated in some patients with
LSD, is being studied . Neonatal LSD screening initiatives and protocols are being developed based on
the common feature of lysosomal enlargement and increase in lysosomal proteins. Immune quantification
assays of protein markers and tandem mass spectrometry for glycosphingolipid and oligosaccharide markers
have been suggested for newborn screening for LSD
In the past decade there have been major advances in therapies for LSD. Bone marrow or hematopoietic
stem cell transplantation and enzyme replacement therapy may benefit selected patients with LSD,
particularly if treatment is begun early in life or if CNS symptoms are minimal
Table 1: LSD for which disease specific therapies are being evaluated
| Bone marrow or hematopoetic stem cell transplantation|
| MPS I, II, III, VI, VII |
| α-Mannosidosis |
| Wolman Disease |
| Metachromatic leukodystrophy |
| Krabbe Disease |
| Mucolipidosis II |
| Neuronal ceroid lipofuscinosis 1|
| Farber Disease |
| Fucosidosis |
| Niemann-Pick C |
| Gaucher Disease |
| Fabry Disease |
| GM1 and GM2 gangliosidosis|
| Enzyme replacement therapy|
| Gaucher Disease |
| Fabry Disease |
| MPS I, II, VI |
| Pompe Disease |
| Niemann-Pick B|
Central to many of these therapies is the Man 6-P receptor pathway which allows enzyme in the blood to be
delivered intracellularly to lysosomes where it can catabolize stored substrate. Gene therapy is likely
on the horizon for LSD and holds the promise of a virtual cure by providing patients with an endogenous
source of enzyme by supplying a normal copy of the gene for the deficient protein.
Animal models have been very important in the evaluation of the effectiveness of such therapies for
. They will continue to provide important information on the safety and impact of new
therapeutic strategies including new enzyme delivery methods, substrate deprivation, neural stem cell and
gene therapy on LSD. Such therapies hopefully will allow more effective treatment of the skeleton and
circumvent the blood-brain barrier to provide therapeutic enzyme to the CNS.
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