DIAGNOSIS
Laboratory findings
●Dermatan and heparan sulfate are present in the urine. Serum assay of IDS activity can also be used.
●A definitive diagnosis is made by assaying for the activity of sulfoiduronate sulfatase in fibroblasts or by demonstrating mutations in the gene.
Differential diagnosis
●Hurler syndrome in type IIA, other storage diseases.
PROPHYLAXIS
●Mucopolysaccharidosis II is an X-linked disorder. Hence, the disease is only transmissible from mother to son. Parents at risk should be informed that there is a 50% chance that a son will be affected and a 50% chance that a daughter will be a carrier. Carrier females do not manifest any signs of the disease. Carrier detection can be done by using direct dye primer sequencing of PCR products.
●Prenatal diagnosis is possible and is at the present time the most effective way to deal with MPS II. Amniocentesis or chorionic villus biopsy is performed in pregnancies where the mother has previously given birth to an affected son. Amniotic cells are cultured and examined for a deficiency of iduronate sulfatase or for mutations in the gene. If such is found, the pregnancy can be interrupted early. It is also possible to measure the levels of iduronate sulfatase in the mother’s serum; these levels rise between the 6th and 12th week if the fetus is normal, but do not increase if the fetus is affected.
TREATMENT
●The physician should offer the parents sympathetic guidance in dealing with the deformities and resultant complications that characterize both forms of Hunter syndrome.
●Genetic counseling and prenatal diagnosis are offered to families with an affected child.
●Surgical treatment is supportive; repair of hernias or orthopedic surgery for skeletal deformities may be necessary. Patients with hydrocephalus and papilledema may require shunting if intracranial pressure is elevated.
●Allogeneic bone marrow transplantation has been tried in several patients with improvement in clinical findings. But it still remains controversial since it often fails to reverse CNS impairment and carries substantial mortality and morbidity.
●Enzyme and gene replacement therapies are under development.
ANESTHESIA CONSIDERATIONS
Administration of a general anesthetic may be complicated by excessive pharyngeal secretions, laryngospasm, cardiac abnormalities, and increased frequency of cardiac arrest, hypoxia or hypotension. Postoperative obstruction or infection may occur in the respiratory tract and may require tracheotomy. Many of these complications may be avoided if large doses of atropine
are given in the preinduction period and if postoperative narcotics are withheld as much as possible.
SUPPORT GROUPS
The Canadian Society for Mucopolysaccharide & Related Disease, Inc. P.O. Box 64714
Unionville, ON L3R 0M9
Phone/Fax (905) 479-8701
National MPS Society, Inc. 17 Kraemer Street Hicksville, NY 11801 (516) 432-1797
Fax: (410) 538-4964
REFERENCES
Beck M, Cole G: Disc oedema in association with Hunter’s syndrome. Ocular histopathological findings. Br J Ophthalmol 68:590–594, 1984.
Braun S, Aronovich E, Anderson R, et al: Metabolic correction and crosscorrection of mucopolysaccharidosis type II (Hunter syndrome) by retroviral-mediated gene transfer and expression of human iduronate- 2-sulfatase. Proc Natl Acad Sci USA 90:11830, 1993.
Caruso R, Kaiser-Kupfer M, Muenzer J, et al: Electroretinographic findings in the mucopolysaccharidoses. Ophthalmology 93:1612, 1986.
Collins MLZ, Traboulsi EI, Maumenee IH: Optic nerve head swelling and optic atrophy in the systemic mucopolysaccharidoses. Ophthalmology 97:1445–1449, 1990.
Hopwood JJ, Bunge S, Morris CP, et al: Molecular basis of mucopolysaccharidosis type II: mutations in the iduronate-2-sulphatase gene. Hum Mutat 2:435–442, 1993.
Legum CP, Schorr S, Berman ER: The genetic mucopolysaccharidosis, type II-A (Hunter syndrome, severe). Ophthalmology 92:1772–1779, 1985.
Narita AS, Russell-Eggitt I: Bilateral epiretinal memebranes: a new finding in Hunter syndrome. Ophthalmic Genetics 17(2):75–78, 1996.
Neufeld EF, Muenzer J: The mucopolysaccharidoses. In: Scriver CR, Beudet AL, Sly WS, Valle D, eds: The metabolic and molecular bases of inherited disease. New York, McGraw-Hill, 1995:2465–2494.
Pan D, Jonsson JJ, Braun SE, et al: Supercharged cells for delivery of recombinant human iduronate-2-sulfatase. Mol Genet Metab 70(3):170–178, 2000.
Peters C, Krivit W: Hematopoietic cell transplantation for mucopolysaccharidosis IIB (Hunter’s syndrome). Bone Marrow Transplantation 25(10):1097–1099, 2000.
Vellodi A, Young E, Cooper A, et al: Long-term follow-up following bone marrow transplantation for Hunter disease. J Inherit Metab Dis 22(5):638–648, 1999.
Vine AK: Uveal effusion in Hunter’s syndrome. Evidence that abnormal sclera is responsible for the uveal effusion syndrome. Retina 6(1):57–60, 1986.
74 MUCOPOLYSACCHARIDOSIS III
277.5
(MPS III, Sanfilippo Syndrome)
Sangeeta Khanna, MD
Cleveland, Ohio
Elias I. Traboulsi, MD
Cleveland, Ohio
The Sanfilippo syndrome, or mucopolysaccharidosis III, is a lysosomal storage disease due to impaired degradation of
III Mucopolysaccharidosis • 74 CHAPTER
135
Metabolism Carbohydrate5 SECTIONof Disorders •
heparan sulfate. Patients with Sanfilippo syndrome have severe central nervous system but only mild somatic disease. Clinical signs become apparent between two and six years of age. The mild somatic features often lead to a significant delay in diagnosis because a storage disease is not suspected. There may be moderate dwarfism, minimal skeletal dysostosis, and moderate hepatosplenomegaly. Some patients present with marked hyperactivity, or with destructive tendencies and behavioral problems. Four non-allelic subtypes, designated A, B, C, and D, may be difficult to distinguish clinically. Type A, however, is most severe, with an earlier onset, more rapid progression of symptoms and earlier death than types B, C or D.
The corneas of patients with MPS III remain clear, but retinal pigmentary degeneration is common. Collins and co-workers found papilledema in 5% of patients and optic atrophy in 14%.
ETIOLOGY/INCIDENCE
The four types of Sanfilippo syndrome can be differentiated by enzymatic assays. N-sulfated glucosamine residues are removed during the degradation of heparan sulfate through the sequential action of four enzymes which are defective in the Sanfilippo syndromes.
●In MPS IIIA, there is a deficiency of heparan N-sulfatase or sulfamidase that maps to chromosome 17q25.3.
●In MPS IIIB, α-N-acetyl-glucosaminidase (NAG) is lacking and maps to chromosome 17q21.
●In MPS IIIC, there is deficiency of acetyl CoA: α-glucosami- nidase located on chromosome 14.
●In MPS IIID the defect is in N-acetyl glucosamine 6- sulfatase located on chromosome 12q14.
COURSE/PROGNOSIS
Mental and neurologic defects progress to extreme degrees within a few years and death usually occurs by 10 to 15 years of age.
DIAGNOSIS/LABORATORY FINDINGS
●Excessive heparan sulfate, but not dermatan sulfate, is excreted in the urine. The MPS urine spot test is positive.
formed on amniotic cells or chorionic villi for all of the enzymes involved in MPS III. If one of the enzymes is found to be deficient, pregnancy can be interrupted early.
TREATMENT
●Genetic counseling is indicated for parents who already have an affected child. They should be informed of the 25% statistical probability of having affected children in future pregnancies.
●Bone marrow transplantation (BMT) has been tried in some patients with some improvement in clinical findings. Successful BMT has been shown to improve systemic health, but not long term retinal function. It should only be used in selected cases with extensive pre-transplantation counseling and clinical assessment and with systematic longterm monitoring.
●Enzyme and gene replacement therapies are under development.
SUPPORT GROUPS
The Canadian Society for Mucopolysaccharide & Related Disease, Inc. P.O. Box 64714
Unionville, ON L3R 0M9
Phone/Fax (905) 479-8701
National MPS Society, Inc. 17 Kraemer Street Hicksville, NY 11801 (516) 432-1797
Fax: (410) 538-4964
REFERENCES
Caruso R, Kaiser-Kupfer M, Muenzer J, et al: Electroretinographic findings in the mucopolysaccharidoses. Ophthalmology 93:1612, 1986.
Collins MLZ, Traboulsi EI, Maumenee IH: Optic nerve head swelling and optic atrophy in the systemic mucopolysaccharidoses. Ophthalmology 97:1445–1449, 1990.
Del Monte MA, Maumenee IH, Green WR, Kenyon KR: Histopathlogy of Sanfilippo’s syndrome. Arch Ophthalmol 101:1255–1262, 1983.
Gliddon BL, Hopwood JJ: Enzyme-replacement therapy from birth delays the development of behavior and learning problems in mucopolysaccharidosis type IIIA mice. Pediatr Res 56(1):65–72, 2004.
Gullingsrud EO, Krivit W, Summers CG: Ocular abnormalities in the mucopolysaccharidoses after bone marrow transplantation. Longer follow-up. Ophthalmology 105(6):1099–1105, 1998.
●A precise diagnosis can be obtained by assaying for the Lavery MA, Green WR, Jabs EW, et al: Ocular histopathology and ultrastruc-
specific enzymes in cultured fibroblasts. |
ture of Sanfilippo’s syndrome, type III-B. Arch Ophthalmol 101:1255– |
|
1262, 1983. |
Differential diagnosis
As the physical features of mucopolysaccharidosis III are usually minimal, this disorder may not be included in the differential diagnosis of a child with progressive central nervous system disorder, leading to a significant delay in diagnosis. The urine of patients suspected of having this disorder should be tested for excess mucopolysaccharides, and skin fibroblasts should be cultured and examined for the enzymatic defect.
Neufeld EF, Muenzer J: The mucopolysaccharidoses. In: Scriver CR, Beudet AL, Sly WS, Valle D, eds: The metabolic and molecular bases of inherited disease. New York, McGraw-Hill, 1995:2465–2494.
Van de Kamp J, Niermeiyer M, Von Figura K, Giesberts M: Genetic heterogeneity and clinical variability in the Sanfillippo syndrome (Types A, B, C). Clin Genet 20:152, 1981.
Yogalingam G, Hopwood JJ: Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: diagnostic, clinical, and biological implications. Hum Mutat 18(4):264–281, 2001.
PROPHYLAXIS
Prenatal diagnosis is possible. Amniocentesis or chorionic villus biopsy is performed in pregnancies where the mother has previously given birth to an affected child. Assays are per-
136
75 MUCOPOLYSACCHARIDOSIS IV
277.5
(Chondro-Osteodystrophy, Keratosulfaturia, Morquio–Brailsford Syndrome, Morquio Syndrome, MPS IV)
F. Hampton Roy, MD, FACS
Little Rock, Arkansas
ETIOLOGY/INCIDENCE
Mucopolysaccharidosis IV (MPS IV) is a progressive autosomal recessive disorder characterized by dwarfism, spondyloepiphyseal and dental anomalies, corneal opacification, and normal intelligence. Although primarily a disease of the anterior segment, posterior pole involvement has recently been described. MPS IV is an enzyme deficiency of N-acetyl-galactosamine-6- sulfate sulfatase (type A) or of β-galactosidase (type B). It results in an abnormal accumulation of keratin sulfate in tissues with excretion in urine.
●Cornea: increase in stromal collagen fibril diameter and bulk density; corneal clouding most likely due to abnormal keratocytes and collagen-free areas.
●Lens: cataracts.
●Anterior chamber, trabecular meshwork: glaucoma.
●Retinal pigment epithelium: arteriolar narrowing, increased photopic b wave implicit time, decreased scotopic b wave amplitude, abnormal electro-oculogram.
●Optic nerve: optic atrophy.
●Brain low-density white-matter lesions, dilated ventricle, basal cisterns, subarachnoid space.
●Patients with MPS IV usually die in their third or fourth decade of life from cor pulmonale caused by the severe abnormalities of the chest and spine.
●Variations in the clinical manifestations are common; mild cases have been encountered.
●Patients with mild forms may survive into their 60s.
DIAGNOSIS
Diagnosis is made by radiographic confirmation by the demonstration of flat vertebrae (platyspondyly universalis) and odontoid hypoplasia, the presence of Reilly’s granules in leukocytes, thin-layer chromatography of abnormal oligosaccharide excretion in urine, and the demonstration of profound deficiency of β-galactosidase activity in cultured fibroblasts. New synthetic fluorimetric substrate has provided a highly effective and sensitive method for the postnatal, prenatal, and retrospective diagnosis of Morquio syndrome type A.
TREATMENT
Systemic
●Methods to regulate the synthesis or to enhance the metabolism or excretion of mucopolysaccharides are not available.
●Direct gene replacement is futuristic.
●Small clinical trials involving enzyme replacement have been carried out.
●To date, the infusion of plasma and purified enzymes and the implantation of cultured fibroblasts and amnion cells (HLA negative) have failed to produce quantitative clinical effects.
COURSE/PROGNOSIS
●Although the classic clinical and radiographic features of Morquio syndrome are present at birth, they become distinctive by 2 years of age.
●Joint laxity and shortness of stature require prompt medical attention.
●Advancing age brings exaggeration of the multiple skeletal abnormalities, with deficient linear growth beyond age 5.
●Cardiac manifestations occur secondary to respiratory failure caused by kyphoscoliosis and restricted chest movements.
●Aortic regurgitation may occur primarily.
●Teeth are severely affected and have thin enamel (type A).
●Subtle corneal changes may appear at an early age but are not usually appreciated until age 4.
●Glaucoma, cataracts, and retinal pigment epithelium changes have been reported.
●Note: retinal findings have been reported only in patients of an advanced age, suggesting that retinal involvement in the disease is mild but progressive and therefore cannot be seen in younger patients but becomes apparent in older patients.
Supportive
●The intelligence of patients with MPS IV is usually normal; with sympathetic guidance, these individuals can achieve age-appropriate levels of education.
●A hearing aid may be of some value in patients with hearing loss from recurrent otitis media.
●Parents of affected children have a 25% risk of having another affected child.
●Prenatal diagnosis can be made by enzyme assay from cultured amniotic fluid cells or by analysis of amniotic fluid MPS derived from fetal tissue.
Surgical
●Prophylactic posterior spinal fusion of the upper cervical spine can be performed to prevent atlantoaxial subluxation or translocation with resultant spinal cord compression and cervical myelopathy.
●Myringotomy can be performed for recurrent otitis media.
●Penetrating keratoplasty is generally not necessary.
PRECAUTIONS
There is no specific treatment for MPS IV. The risk of com-
●Despite normal intelligence, patients with Morquio synplications associated with anesthesia and postoperative resdrome who reach advanced age show characteristic piratory obstruction must be appreciated before even simple
computed tomography scan findings suggesting mucopoly- |
procedures are undertaken. Hyperextension should be |
saccharide deposition in cortical matter. |
avoided. |
IV Mucopolysaccharidosis • 75 CHAPTER
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Metabolism Carbohydrate5 SECTIONof Disorders •
SUMMARY
Morquio syndrome is a multisystem disorder whose hallmark is severe skeletal deformity. The ocular involvement is usually mild and confined to the anterior segment, with corneal clouding being the most common presenting ocular complaint. Management is inevitably multidisciplinary, with the primary care physician playing the primary role in the coordination of services. The major treatment issue centers on the prevention of cervical myelopathy. Prophylactic surgical intervention is recommended by many, but the timing and selection of patients are unclear. Parents of affected children need considerable support, and The Society for Mucopolysaccharide Diseases has afforded parents and affected individuals a much needed outlet for emotional and financial support.
SUPPORT GROUP
The Society for Mucopolysaccharide Diseases 55 Hill Avenue
Amersham, Bucks, UK HP6 5BX
REFERENCES
Cahane M, Treister G, Abraham FA, Melamed S: Glaucoma in siblings with Morquio syndrome. Br J Ophthalmol 74:382–383, 1990.
Dangel ME, Tsou BH: Retinal involvement in Morquio syndrome. Ann Ophthalmol 17:349–354, 1985.
Iwamoto M, Nawa Y, Maumenee IH, et al: Ocular histopathology and ultrastructure of Morquio syndrome. Graefes Arch Clin Exp Ophthalmol 228:342–349, 1990.
Leslie T, Lois N, Christopoulou D, et al: Photodynamic therapy for inflammatory choroidal neovascularisation unresponsive to immunosuppression. Br J Ophthalmol 89(2):147–150, 2005.
Leslie T, Siddiqui MA, Aitken DA, et al: Morquio syndrome electron microscopic findings. Br J Ophthalmol 89(7):925–926, 2005.
Northover H, Cowie RA, Wraith JE: Mucopolysaccharidosis type IV A (Morquio syndrome): Clinical review. J Inher Metab Dis 19:357–365, 1996.
Rawe IM, Leonard DW, Meek KM, Zabel RW: X-ray diffraction and transmission electron microscopy of Morquio syndrome type A cornea: Structural analysis. Cornea 16:369–376, 1997.
Rekhi GS: Morquio syndrome (MPS IV): a case report. Indian J Ophthalmol 39:78–81, 1991.
Zhao H, Van Diggelen OP, Kleijer WJ, Li P: Enzymatic diagnosis of Morquio A syndrome with a new fluorimetric substrate. Chin Med Sci J 6:9–13, 1991.
76 MUCOPOLYSACCHARIDOSIS VI
277.5
(MPS VI, Maroteaux–Lamy Syndrome)
La-ongsri Atchaneeyasakul, MD
Bangkok, Thailand
Richard G. Weleber, MD
Portland, Oregon
ETIOLOGY/INCIDENCE
Mucopolysaccharidosis VI (MPS VI) is a rare autosomal recessive disorder characterized by the intralysosomal storage and
excessive urinary excretion of the glycosaminoglycan dermatan sulfate or chondroitin sulfate B. The syndrome is caused by a deficiency of the lysosomal enzyme sulfogalactosamine sulfatase (N-acetyl-galactosamine-4-sulfatase or arylsulfatase B, ASB). Clinical phenotypes have been described as mild, intermediate, or severe based on the age at onset, the organ of involvement, and the rate of disease progression. After the description of the arylsulfatase B gene, several mutant alleles have been identified suggesting a wide genetic heterogeneity of the syndrome.
COURSE/PROGNOSIS
Recent studies demonstrated some genotype/phenotype correlations that may contribute to the prediction of disease progression and the evaluation of various therapeutic approaches. The physical findings of MPS VI resemble those of MPS IH with respect to growth retardation, skeletal deformities, and coarse facial features; however, intellectual development is normal. A prominent forehead and sternal protrusion are frequently noted soon after birth. Restriction of joint motion may begin by the first year. Growth retardation is first noted at the age of 2 or 3 years, and skeletal growth may cease entirely after 8 years resulting in dwarfism. By the sixth year, all patients have hepatomegaly, and about half have enlarged spleens. Deafness and inguinal hernias are common. Most patients have corneal clouding, which can interfere with vision and adversely affect psychomotor development. Cardiac involvement (aortic and mitral valvular stenosis) is frequent and, with respiratory complications, is the most serious threat to patients. Generally, the life span is longer than that for patients with MPS IH, although with the severe phenotype, survival past the mid-20s is rare.
DIAGNOSIS
Clinical signs and symptoms
The significant ocular manifestations of MPS VI are corneal clouding, which is moderate in degree and develops early; glaucoma; and optic atrophy. Significant visual loss from corneal clouding usually develops during the first decade of life. The mechanism of glaucoma may be secondary angle closure due to thickening of the cornea or secondary open angle due to the obstruction of the trabecular meshwork by mucopolysaccharides. Papilledema has been reported and is thought to be associated with hydrocephalus.
Ocular or periocular
●Choroid: thinning.
●Ciliary body: acid mucopolysaccharide deposits.
●Cornea: acid mucopolysaccharide deposits in the epithelium, lamellar clefts in the anterior stroma, cytoplasm of keratocytes and endothelial cells, clouding, opacity, thickening.
●Eyebrows: bushy, coarse.
●Optic nerve: atrophy, cupping, papilledema, thickening of the optic nerve sheaths.
●Retina: detachment, macular edema, vascular tortuosity.
●Sclera: acid mucopolysaccharide deposits, thickening.
●Other: coarse eyelashes, decreased visual acuity, glaucoma.
138
TREATMENT
Systemic
Bone marrow transplantation
Bone marrow transplantation (BMT) in newborn rats with MPS VI may prevent many pathologic and clinical findings but still has unpredictable effects on the skeletal abnormalities. BMT has been tried in patients with several forms of mucopolysaccharidoses, including MPS VI, with subsequent normalization of ASB activity in white blood cells and glycosaminoglycans excretion. The treatment also improved cardiac and respiratory functions and the ultrastructural appearance of the liver and resulted in a decrease in hepatosplenomegaly and an increase in joint mobility. There is no change in bone pathology, facial appearance, and short stature. Clearing of corneal cloudiness, which has occurred with BMT in other forms of MPS, has not been observed in MPS VI. However, a follow-up of the corneal transplants after BMT demonstrated clear corneal grafts 13 years postoperatively. Considering the risks, high expense, and questionable outcome, BMT should be considered experimental and restricted to carefully selected and monitored patients.
ledema may be relieved through the shunting of cerebrospinal fluid.
PRECAUTIONS
Atlantoaxial subluxation can occur as a result of hypoplasia of the odontoid process. In addition, neurologic deterioration from myelopathy due to thickening of the dura of the cervical spinal cord and consequent cord compression has been reported. Somatosensory evoked potential testing is useful to detect subclinical impairment of the cervical cord. Early surgical decompression seems to be beneficial.
COMMENTS
One of the most outstanding features of MPS VI is the normal intellectual capacity of the patients. They usually attend regular schools and pass their examinations without difficulties, although visual and physical handicaps eventually impede their psychomotor performance.
Enzyme replacement therapy
An ongoing Phase I/II study of recombinant human N-acetyl- galactosamine-4-sulfatase in MPS VI patients has recently reported that this treatment was well-tolerated and reduced lysosomal storage as evidenced by a dose-dependent reduction in urinary glycosaminoglycan. Functional status also improved as shown by an increase in distance walked, stair-climbing ability, shoulder range of motion, and decrease in pain and arthritis severity scores.
Gene therapy
Another experimental approach is the use of hematopoietic stem cell gene therapy through the construction of a retroviral vector containing the full-length human ASB cDNA and the use of this vector to transduce bone marrow cells in vitro from patients with MPS VI. Recent study in MPS VI cats showed that AAV-mediated subretinal delivery of the feline 4-sulfatase cDNA reduced lysosomal accumulation in the retinal pigment epithelial cells.
Supportive
The physician should offer sympathetic guidance in helping the parents deal with the skeletal deformities that develop in these patients. Parents should be informed of available inpatient clinic care facilities. Genetic counseling should be provided to parents and other potential carriers, as well as to patients who reach childbearing age. Both parents of an affected child are carriers of the deficient gene; however, because the gene defect is detectable in amniotic cell cultures, prenatal diagnosis is possible.
Surgical
Surgical treatment is supportive, with repair of hernias and hydroceles, orthopedic surgery for skeletal deformities, or adenoidectomy to provide relief from the persistent nasal discharge, as indicated. Penetrating keratoplasty or lamellar corneal grafting has been performed for significant corneal clouding. Although mucopolysaccharide can reaccumulate in corneal grafts within 1 year after transplantation, there are some patients with clear grafts and good visual outcomes after 5 years of follow-up. Hydrocephalus and associated papil-
REFERENCES
Boor R, Miebach E, Bruhl K, Beck M: Abnormal somatosensory evoked potentials indicate compressive cervical myelopathy in mucopolysaccharidoses. Neuropediatrics 31:122–127, 2000.
Fillat C, Simonaro CM, Veyati PL, et al: Arylsulfatase B activities and glycosaminoglycan levels in retrovirally transduced mucopolysaccharidosis type VI cells. J Clin Invest 98:497–502, 1996.
Harmatz P, Whitley CB, Waber L, et al: Enzyme replacement therapy in mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). J Pediatr 144:574–580, 2004.
Ho TT, Maguire AM, Aguirre GD, et al: Phenotypic rescue after adenoassociated virus-mediated delivery of 4-sulfatase to the retinal pigment epithelium of feline mucopolysaccharidosis VI. J Gene Med 4:613–621, 2002.
Jin WD, Jackson CE, Desnick RJ, Schuchman EH: Mucopolysaccharidosis type VI: Identification of three mutations in the arylsulfatase B gene of patients with the severe and mild phenotypes provides molecular evidence for genetic heterogeneity. Am J Hum Genet 50:795–800, 1992.
Litjens T, Brooks DA, Peters C, et al: Identification, expression, and biochemical characterization of N-acetylgalactosamine-4-sulfatase mutations and relationship with clinical phenotype in MPS-VI patients. Am J Hum Genet 58:1127–1134, 1996.
Neufeld EF, Muenzer J: The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds: The metabolic and molecular bases of inherited disease. 7th edn. New York, McGraw-Hill, 1995: II:2465–2494.
Simonaro CM, Haskins ME, Kunieda T, et al: Bone marrow transplantation in newborn rats with mucopolysaccharidosis type VI. Transplantation 63:1386–1393, 1997.
Ucakhan OO, Brodie SE, Desnick R, et al: Long-term follow-up of corneal graft survival following bone marrow transplantation in the Maro- teaux-Lamy syndrome. CLAO J 27:234–237, 2001.
Van Dyke DL, Fluharty AL, Schafer IA, et al: Prenatal diagnosis of Maro- teaux-Lamy syndrome. Am J Med Genet 8:235–242, 1981.
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