Ocular

●If lens opacifies and becomes visually significant or there are total cataracts, lens extraction indicated:

● Maximize visual potential.

●For vitreous hemorrhage, possible surgical intervention.

SUPPORT GROUP

Parents of Galactosemic Children Inc. 2871 Stagecoach Drive

Valley Springs, CA 95252 (209) 772-2449

E-mail: www.galactosemie.org

REFERENCES

Beigi B, O’Keefe MO, Bowell R, et al: Ophthalmic findings in classical galactosaemia: prospective study. Br J Ophthalmol 77:162–164, 1993.

Burke JP, O’Keefe M, Bowell R, Naughten ER: Ophthalmic findings in classical galactosemia: a screened population. J Pediatr Ophthalmol Strabismus 26:165–168, 1989.

Gitzelmann R: Hereditary galactokinase deficiency, a newly recognized cause of juvenile cataracts. Pediatr Res 1:14, 1967.

Levy HL, Brown AE, Williams SE, de Juan E: Vitreous hemorrhage as an ophthalmic complication of galactosemia. J Pediatr 129:922–925, 1996.

Mason HH, Turner ME: Chronic galactosemia. Am J Dis Child 50:359, 1935.

Ridel KR, Leslie ND, Gilbert DL: An updated review of the long-term neurological effects of galactosemia. Pediatr Neurol 33(3):153–161, 2005.

Schweitzer-Krantz S: Early diagnosis of inherited metabolic disorders towards improving outcome: the controversial issue of galactosaemia. Eur J Pediatr 162 Suppl 1:S50–S53, 2003.

Stambolian D: Galactose and cataract. Surv Ophthalmol 32:333–349, 1988.

Walter JH, Collins JE, Leonard JV: Recommendations for the management of galactosaemia. UK Galactosaemia Steering Group. Arch Dis Child 80(1):93–96, 1999.

teoglycans in abnormal vacuolated stromal cells and nearby stroma. To date, more than 46 mutations of the IDUA gene have been defined for MPS I. Since the cloning of this gene, mutation analysis has also provided some molecular explanations for the range of MPS I phenotypes. The overall frequency is 1 per 100,000 live births worldwide. Severe Hurler syndrome and mild Scheie’s disease are extremes of the clinical spectrum caused by different IDUA mutations. Children affected by Hurler syndrome may develop normally for the first few months, but typical Hurler manifestations begin to appear in the first or second year of life. The primary manifestations include skeletal abnormalities, umbilical and inguinal hernias, enlargement of the spleen and liver, and mental retardation. Clouding of the cornea is present in all patients with this disease. Prenatal diagnosis is possible by measuring the iduronidase activity in cultured amniotic cells and in chorionic villi.

COURSE/PROGNOSIS

●Slowly progressive, if untreated it usually leads to death before the age of 14 years.

●Death commonly occurs from cardiac failure and chronic respiratory infection, although early death during infancy has occurred after endocardial fibroelastosis.

●There is a wide range of clinical phenotypes in MPS I, which makes the prediction of disease severity and genetic counseling difficult.

DIAGNOSIS

Early diagnosis is essential to achieve an acceptable outcome after bone marrow transplantation (BMT). The diagnosis is suggested by certain clinical and radiologic findings, as well as by a urine screening test, and it should be confirmed with enzyme assays of cultured fibroblasts or leukocytes. By the end of the first year of life, the clinical diagnosis becomes evident. The following are the most common clinical and radiologic findings associated with MPS I.

71 MUCOPOLYSACCHARIDOSIS IH

277.5

(Dysostosis Multiplex, Hurler Syndrome,

MPS IH, Pfaundler–Hurler Syndrome)

Fernando H. Murillo-Lopez, MD

La Paz, Bolivia

ETIOLOGY/INCIDENCE

Mucopolysaccharidosis type I (MPS I), the most common of the mucopolysaccharidoses, is an autosomal recessive disease caused by mutations in the α-L-iduronidase (IDUA) gene (localized to the distal short arm of chromosome 4 at 4p16) α-L- iduronidase is the enzyme responsible for the breakdown of dermatan sulfate and heparan sulfate. As a result of this mutation, abnormal intracellular accumulations of glycosaminoglycans and interference with normal cell function take place. Corneal clouding results from abnormal accumulation of pro-

Clinical signs and symptoms

Systemic

Within 3 months of age

●Recurrent rhinitis.

●Recurrent inguinal hernias.

Within 6 months of age

●Skeletal abnormalities.

●Gibbus formation.

●Asymmetric chest.

●Prominent sternum.

●Bulging forehead.

After 9 months

●Decreased hearing secondary to recurrent ear infections.

●Coarse facial appearance.

●Hepatomegaly.

All age groups

●Nasal obstruction, sinus polyps, multiple ear, nose, and throat operations.

●Recurrent upper respiratory and sinus infections.

●Macrocephaly (secondary to calvarial thickening and hydrocephalus), microcephaly, hydrocephalus, craniosynostosis, kyphosis, scoliosis.

●Dysostosis multiplex, a group of skeletal abnormalities consisting of a large skull with a deep elongated, J-shaped sella; thickened, oar-shaped ribs; deformed, hook-shaped lower thoracic and upper lumbar vertebrae; pelvic dysplasia; shortened tubular bones with expanded diaphyses and dysplastic epiphyses.

COMPLICATIONS

●The administration of general anesthesia is complicated by excessive pharyngeal secretions, laryngospasm, cardiac abnormalities, increased frequency of cardiac arrest, hypoxia, and hypotension.

●Postoperative obstruction or infection may occur in the respiratory tract and requires tracheotomy.

Ocular

●Ocular manifestations include peripheral/central corneal clouding, megalocornea, buphthalmos, coarse eyelashes, lid edema, ptosis, retinal pigmentary degeneration, optic nerve atrophy, hypertelorism, chronic open-angle glaucoma, acute and chronic angle-closure glaucoma, goniodysgenesis, anisocoria and abnormal electroretinogram.

Laboratory findings

●Blood smears: abnormal cytoplasmic inclusions in lymphocytes.

●Urine: increased excretion of dermatan sulfate and heparan sulfate.

●Cultured cells: elevated iduronidase activity in leukocytes, cultured fibroblasts, cultured amniotic cells, or chorionic villus cells.

●Predicting disease severity in mucopolysaccharidosis I patients may be possible using a biochemical analysis of cultured skin fibroblasts.

TREATMENT

●Laronidase enzyme replacement therapy with aldurazyme

(Genzyme), a polymorphic variant of the human enzyme α-L-iduronidase has shown significant improvement in walking capacity and pulmonary function in clinical trials.

●Allogeneic bone marrow transplantation has been an effective treatment for MPS I.

●Most patients who survive at least 5 years after BMT show an arrest or slowing down of psychomotor regression, although dysostosis multiplex continues to progress.

●Early diagnosis is essential in achieving an acceptable outcome after BMT.

●Since cloning of the IDUA gene, mutation analysis has provided more information that facilitates the selection and evaluation of patients undergoing experimental treatment protocols, including BMT.

●Due to a lack of matched related donors and unacceptable morbidity rates for matched unrelated transplantation, BMT is not available to all patients with Hurler syndrome.

●Transfer and expression of the normal gene in autologous bone marrow using techniques such as retroviral gene transfer into human bone marrow may offer the prospect for gene therapy in the near future.

●Surgical supportive treatment includes the repair of hernias and hydroceles, orthopedic surgery for skeletal deformities, and adenoidectomy to provide relief from persistent upper airway obstruction.

●Ocular treatment includes penetrating keratoplasty and trabeculectomy for corneal opacification and glaucoma, respectively.

COMMENTS

Understanding of the genotype/phenotype correlation in the mucopolysaccharidoses has increased significantly in the past 10 years. A complex picture of molecular heterogeneity has emerged and has provided some important clues into the structure and function of the IDUA gene. In the future, this knowledge will contribute to the development of successful gene therapy for these disorders. Until then, patients with Hurler syndrome still have a dismal prognosis, and their only hope lies in enzyme replacement therapy and/or early BMT. For this reason, making a timely clinical diagnosis is very important in this disorder, and a urine test for glycosaminoglycan excretion should be performed if there is any clinical suspicion, even in the presence of normal developmental progress.

REFERENCES

Cleary MA, Wraith JE: The presenting features of mucopolysaccharidosis type IH (Hurler syndrome). Acta Paediatr 84:337–339, 1995.

Fairbairn LJ, Lashford LS, Spooncer E, et al: Long-term in vitro correction of alpha-L-iduronidase deficiency (Hurler syndrome) in bone marrow. Proc Natl Acad Sci USA 93:2025–2030, 1996.

Francois J: Ocular manifestations of the mucopolysaccharidoses. Ophthalmologica 169:345–361, 1974.

Fuller M, Brooks DA, Evangelista M, et al: Prediction of neuropathology in mucopolysaccharidosis I patients. Mol Genet Metab. 84(1):18–24, 2005.

Grewal SS, Wynn R, Abdenur JE, et al: Safety and efficacy of enzyme replacement therapy in combination with hematopoietic stem cell transplantation in Hurler syndrome. Genet Med 7(2):143–146, 2005.

Huang Y, Bron AJ, Meek KM, et al: Ultrastructural study of the cornea in a bone marrow-transplanted Hurler syndrome patient. Exp Eye Res 62:377–387, 1996.

Scott HS, Bunge S, Gal A, et al: Molecular genetics of mucopolysaccharidosis type I: Diagnostic, clinical, and biological implications. Hum Mutat 6:288–302, 1995.

Stephen JM, Stevens JL, Wenstrup RJ, et al: Mucopolysaccharidosis I presenting with endocardial fibroelastosis of infancy. Am J Dis Child 143:782–784, 1989.

Vellodi A, Young EP, Cooper A, et al: Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centres. Arch Dis Child 76:92–99, 1997.

Wraith JE: The first 5 years of clinical experience with laronidase enzyme replacement therapy for mucopolysaccharidosis I. Expert Opin Pharmacother 6(3):489–506, 2005.

72 MUCOPOLYSACCHARIDOSIS IH/S

277.5

(Hurler–Scheie Syndrome, MPS IH/S)

Fernando H. Murillo-Lopez, MD

La Paz, Bolivia

ETIOLOGY/INCIDENCE

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease caused by mutations in the α-L-iduronidase (IDUA) gene (localized to the distal short arm of chromosome 4) that result in abnormal intracellular accumulations of glycosaminoglycans and interference with normal cell function. Corneal clouding results from abnormal accumulation of proteoglycans in abnormal vacuolated stromal cells and nearby stroma. To date, more than 46 mutations of the IDUA gene have been defined for MPS I. Since the cloning of this gene, mutation analysis has also provided some molecular explanations for the range of MPS I phenotypes. Severe Hurler syndrome and mild Scheie’s disease are extremes of the clinical spectrum caused by different IDUA mutations. Novel mutations are still being reported for Hurler–Scheie syndrome including single base changes. Patients with MPS IH/S have a phenotype intermediate between those of IH and IS that is caused by homozygous mutations or double heterozygosity of different IDUA gene mutations. The primary manifestations of MPS IH/S include skeletal abnormalities, enlargement of the spleen and liver, umbilical and inguinal hernias, and corneal opacities. Micrognathia and severe acne are features peculiar to this form of mucopolysaccharidosis; clouding of the cornea is also present in all patients with this disease. Prenatal diagnosis is possible by measuring the iduronidase activity in cultured amniotic cells and chorionic villi.

Clinical signs and symptoms

Systemic

●Mild to severe mental retardation.

●Recurrent rhinitis, nasal obstruction, sinus polyposis, multiple ear, nose, and throat operations.

●Recurrent inguinal hernias, hepatomegaly.

●Skeletal abnormalities, gibbus formation, asymmetric chest, prominent sternum, kyphosis, scoliosis, bulging forehead.

●Decreased hearing secondary to recurrent ear infections.

●Coarse facial appearance, coarse and bushy eyebrows.

●Recurrent upper respiratory and sinus infections.

●Macrocephaly (secondary to calvarial thickening and hydrocephalus), microcephaly, hydrocephalus, craniosynostosis.

●Grouped papules on the extensor surfaces on the upper portions of the arms and legs, progressive flexion contractures.

●Dysostosis multiplex, a group of skeletal abnormalities consisting of a large skull with a deep elongated, J-shaped sella; thickened, oar-shaped ribs; deformed, hook-shaped lower thoracic and upper lumbar vertebrae; pelvic dysplasia; and shortened tubular bones with expanded diaphyses and dysplastic epiphyses.

Ocular

●Ocular manifestations include peripheral/central corneal clouding, megalocornea, buphthalmos, coarse eyelashes, lid edema, ptosis, retinal pigmentary degeneration, optic nerve atrophy, hypertelorism, chronic open-angle glaucoma, acute and chronic angle-closure glaucoma, goniodysgenesis, anisocoria and abnormal electroretinogram.

Laboratory findings

●Blood smears: abnormal cytoplasmic inclusions in lymphocytes.

●Urine: increased excretion of dermatan sulfate and heparan sulfate.

●Cultured cells: elevated iduronidase activity in leukocytes, cultured fibroblasts, cultured amniotic cells, or chorionic villus cells.

COURSE/PROGNOSIS

●Slowly progressive; if untreated the life expectancy of these patients is usually into the 20s.

●Mental deficiency and dwarfism are less severe than in Hurler syndrome, although the patterns of radiographic changes are similar.

●Death commonly occurs after protracted cardiac failure.

●There is a wide range of clinical phenotypes in MPS I (including MPS IH/S), which makes the prediction of disease severity and genetic counseling difficult.

DIAGNOSIS

Early diagnosis is essential to achieve an acceptable outcome after bone marrow transplantation (BMT). The diagnosis is suggested by certain clinical and radiologic findings, as well as by a urine screening test, and it should be confirmed with enzyme assays of cultured fibroblasts or leukocytes. The following are the most common clinical and radiologic findings associated with MPS I.

TREATMENT

●To date, allogeneic BMT has been the only form of effective treatment for MPS I.

●BMT must be done at an early stage of the disease to achieve an acceptable outcome.

●Since cloning of the IDUA gene, mutation analysis has provided more information that facilitates the selection and evaluation of patients undergoing experimental treatment protocols, including BMT.

●Transfer and expression of the normal gene in autologous bone marrow using new techniques such as retroviral gene transfer into human bone marrow may offer the prospect for gene therapy in the near future.

●Treatment with recombinant human α L-iduronidase (laronidase) in patients with mucopolysaccharoridosis I is being reported as successful and well tolerated, particularly in the more severely affected patients.

●Surgical supportive treatment includes the repair of hernias and hydroceles, orthopedic surgery for skeletal deformities, and adenoidectomy to provide relief from persistent upper airway obstruction.

COMPLICATIONS

●The administration of general anesthesia is complicated by excessive pharyngeal secretions, laryngospasm, cardiac abnormalities, increased frequency of cardiac arrest, hypoxia and hypotension.

●Postoperative obstruction or infection may occur in the respiratory tract and requires tracheotomy.

COMMENTS

Hurler syndrome and Scheie syndrome share a common metabolic defect; in both, the enzymatic deficiency is α-L- iduronidase. The mutation in both is presumed to be allelic, and thus it is thought that the inheritance of a Hurler gene and a Scheie gene results in a genetic compound with a phenotype intermediate in severity between those of the Hurler and Scheie syndromes: the Hurler–Scheie syndrome, or MPS IH/S. During the past decade, understanding of the genotype/ phenotype correlation in the mucopolysaccharidoses has increased significantly, and a complex picture of molecular heterogeneity has emerged. Mutation analysis continues to provide some important clues into the structure and function of the IDUA gene, and in the near future, this knowledge will lead to the development of definitive gene therapy for these disorders.

REFERENCES

Francois J: Ocular manifestations of the mucopolysaccharidoses. Ophthalmologica 169:345–361, 1974.

Girard B, Hoang-Xuan T, D’Hermies F, et al: Mucopolysaccharidose de type I, phenotype Hurler-Scheie avec atteinte oculaire: Etude clinique et ultrastructurale. Journal Francais d’ Ophthalmologie 17:286–295, 1994.

Hein LK, Bawden M, Muller VJ, et al: Alpha-L-iduronidase premature stop codons and potential read-through in mucopolysaccharidosis type I patients. J Mol Biol 338(3):453–462, 2004.

MacArthur CJ, Gliclich R, McGill TJ, et al: Sinus complications in mucopolysaccharidosis IH/S (Hurler-Scheie syndrome). Int J Pediatr Otorhinolaryngol 26:79–87, 1993.

Mullaney P, Awad AH, Millar L: Glaucoma in mucopolysaccharidosis 1-H/S. J Pediatr Ophthalmol Strabismus 33:127–131, 1996.

Rimoin DL, Connor JM, Pyeritz RE, eds: Emery and Rimoin’s principles and practice of medical genetics. 3rd edn. New York, Churchill Livingstone, 1996:2071–2079.

Schiro JA, Mallory SB, Demmer L, et al: Grouped papules in Hurler-Scheie syndrome. J Am Acad Dermatol 35(5 pt 2):868–870, 1996.

Scott HS, Ashton LJ, Egre JH, et al: Chromosomal localization of the human alpha-L-iduronidase gene (IDUA) to 4p16.3. Am J Hum Genet 47:802–807, 1990.

Scott HS, Litjens T, Nelson PV, et al: Identification of mutations in the alpha-L-iduronidase gene (IDUA) that cause Hurler and Scheie syndromes. Am J Hum Genet 53:973–986, 1993.

Tieu PT, Bach G, Matynia A, et al: Four novel mutations underlying mild or intermediate forms of alpha-L-iduronidase deficiency (MPS IS and MPS IH/S). Hum Mutat 6(1):55–59, 1995.

Vellodi A, Young EP, Cooper A, et al: Bone marrow transplantation for mucopolysaccharidosis type I: Experience of two British centres. Arch Dis Child 76:92–99, 1997.

73 MUCOPOLYSACCHARIDOSIS II

277.5

(Hunter Syndrome, MPS II)

Sangeeta Khanna, MD

Cleveland, Ohio

Elias I. Traboulsi, MD

Cleveland, Ohio

Mucopolysaccharidosis II is the only known X-linked disorder of mucopolysaccharide metabolism. All others are inherited in an autosomal recessive fashion. Hunter syndrome is caused by mutations in the iduronate-2-sulfatase (IDS) gene. IDS deficiency causes accumulation of undegraded dermatan and heparan sulfate in various tissues and organs. The disease is categorized as severe (type A) with substantial neurological dysfunction, and mild (type B) in which neurological impairment is not prominent. In the severe form (MPS IIA), mental retardation and neurologic changes are almost indistinguishable from those of mucopolysaccharidosis I-H or Hurler syndrome; they include gargoyle-like facies, dwarfism, hepatosplenomegaly, deafness, and death by age 15 years. In the mild type (MPS IIB), intelligence is not impaired, patients survive into adulthood and even procreate. Patients with MPS II have characteristic pebbly, ivory colored skin lesions over the back, neck, scapula, and thighs.

Corneal clouding is usually absent early in type B, although deposits of acid mucopolysaccharides are found histologically, even in clinically clear corneas. All patients have a pigmentary retinopathy with a severely reduced electroretinogram. This leads to visual impairment of varying degrees in all patients. About 20% of patients with Hunter syndrome may have elevated and blurred optic disc margins in the absence of elevated intracranial pressure. This is thought to result from compression of optic nerve fibers at the lamina cribrosa by a sclera that is thickened with mucopolysaccharides. This chronic papilledema leads to optic atrophy in some patients. Other rarely reported ocular findings include epiretinal membranes and uveal effusion syndrome secondary to scleral thickening.

ETIOLOGY

●The incidence of MPS II is 1 : 132,000 male newborns in the United Kingdom, and 1 : 34,000 in Israel.

●The two types of Hunter syndrome are allelic and are caused by mutations at the X-linked locus for the enzyme iduronate sulfate sulfatase. The gene is located on Xq28, distal to the fragile X site. Gene mutation analysis is possible.

COURSE/PROGNOSIS

●In MPS IIA, death usually occurs prior to the age of 15 years.

●In the milder type B, survival may extend past the age of 45. One patient has lived to age 87.