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Combined Hurler and Sanfilippo syndrome in a sibling pair
Molecular Genetics and Metabolism 103 (2011) 135–137
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y m g m e
Combined Hurler and Sanfilippo syndrome in a sibling pair Angela Sun a,⁎, John J. Hopwood b, Jerry Thompson c, Stephen D. Cederbaum d a
UCLA Intercampus Medical Genetics Training Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA Lysosomal Diseases Research Unit, A Research Centre of SA Pathology, Women's and Children's Hospital, North Adelaide, SA, Australia c Department of Genetics, University of Alabama at Birmingham, AL, USA d Departments of Psychiatry, Pediatrics and Human Genetics, UCLA Center for the Health Sciences, Los Angeles, CA, USA b
a r t i c l e
i n f o
Article history: Received 28 December 2010 Received in revised form 16 February 2011 Accepted 16 February 2011 Available online 22 February 2011 Keywords: Hurler syndrome Sanfilippo syndrome Enzyme replacement therapy Psychosocial issues
a b s t r a c t The mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by defects in the enzymes involved in the degradation of glycosaminoglycans. Hurler syndrome (MPS I) and Sanfilippo syndrome (MPS III) are among the more common diseases in the group, each occurring with an incidence of approximately 1 in 100,000. We present a case of siblings, born of a consanguineous union, affected with both MPS I and MPS IIIa. The diagnoses were confirmed with fibroblast enzyme assays and sequence analysis of the genes, which identified homozygous mutations in IDUA and SGSH. We discuss their clinical features and course and examine the psychosocial aspects of their case, specifically, the decision-making process that the medical team and family faced regarding treatment with enzyme replacement therapy. © 2011 Elsevier Inc. All rights reserved.
1. Introduction The mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by defects in the enzymes involved in the degradation of glycosaminoglycans. Hurler syndrome and Sanfilippo syndrome are among the more common diseases in the group, each occurring with an incidence of approximately 1 in 100,000 [1,2]. Individuals with Hurler syndrome or MPS I have deficiency of the enzyme alpha-L-iduronidase and present with developmental delay, coarse facial features, upper airway obstruction, respiratory infections, cardiac disease, and hepatosplenomegaly [3]. There are four subtypes of Sanfilippo syndrome or MPS III, all of which are caused by deficiency of enzymes involved in the breakdown of heparan sulfate. Patients with MPS III typically manifest with neurologic rather than somatic symptoms such as severe behavioral problems, poor sleep, and progressive neurological deterioration [3]. We present a case of siblings affected with both MPS I and MPS III and discuss their clinical features and course. 2. Case reports 2.1. Case 1 The proband is an 8-year-old male of Mexican origin who was the product of an uncle–niece union. He was born at 32 weeks gestational age to a 20-year old gravida 1 para 1 mother via normal spontaneous vaginal delivery. His birth weight was 3 pounds and 12 ounces. During
⁎ Corresponding author at: 8700 Beverly Blvd, PACT 4, Los Angeles, CA 90048, USA. E-mail address: [email protected] (A. Sun). 1096-7192/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2011.02.011
the first year of life, he was noted to have developmental delay and coarse facial features. He was clinically diagnosed with Hurler syndrome at age 1.5 years. Urinary quantitation of glycosaminoglycans showed 127 mg/g creatinine of uronic acid by the orcinol reaction (nl. 10.7 ± 8.0) and 449 mg/g creatinine by the carbazole reaction (nl. 16.9 ± 9.9), giving a carbazole to orcinol ratio of almost 3, which is indicative of excess heparan sulfate as compared with dermatan sulfate. The electrophoresis which revealed a strong band of heparan sulfate and slightly less chondroitin sulfate was confirmatory of this conclusion. Nsulfated hexosamine was 126 mg/g creatinine (nl. 15.8 ± 12). Enzyme analysis on fibroblasts showed 10% residual alpha-L-iduronidase activity and no detectable activity for heparan N-sulfatase. Molecular genetic testing revealed a homozygous c.923TN C (L308P) mutation in the IDUA gene, which has not been previously reported, and a homozygous c.268G N A (G90R) mutation in the SGSH gene, a known pathogenic variant. Thus, he was diagnosed with combined Hurler syndrome and Sanfilippo syndrome type A. During early childhood, the patient had significant problems with gastroesophageal reflux due to a hiatal hernia. He underwent a Nissen fundoplication and a later revision. He also had an umbilical hernia repair. He had multiple hospital admissions for pneumonia and asthma exacerbations. He also had recurrent otitis media, and pressure equalization tubes were placed on multiple occasions. He developed bilateral moderate to severe hearing loss and was prescribed hearing aids. He had a tonsillectomy and adenoidectomy at age 5 years, after which his breathing improved. An abdominal ultrasound at 5 years of age showed an enlarged liver measuring 14.1 cm. His spleen remained normal in size. An echocardiogram at 17 months of age showed mild concentric left ventricular hypertrophy, and at 4 years of age showed a minimal septal bulge into the
136
A. Sun et al. / Molecular Genetics and Metabolism 103 (2011) 135–137
left ventricular outflow tract and otherwise normal cardiac anatomy and function. An MRI of the brain at age 2 years was normal. He reportedly had a normal ophthalmologic examination at 3 years of age, and at age 8 has not developed corneal clouding. The patient had mild orthopedic complications. A skeletal survey at 2 years of age showed early signs of dysostosis multiplex including a J-shaped sella, short and slightly expanded metacarpal bones with thin cortices, and a narrow iliac base with rounded iliac wings. A chest X-ray at age 7 revealed paddle-shaped ribs and short, thickened clavicles. At age 4 years, he began to have increasing joint stiffness, most notably in his ankles, which resulted in toe-walking. He underwent a heel cord release when he was 6 years old. With age, he developed contractures at the knees for which he was prescribed braces. He began losing his ability to ambulate between ages 6 and 7 years. In terms of physical growth, the patient's height remained in the 10–50th percentiles up to age 6, after which his linear growth began to fall off. His weight was at or above the 90th percentile between ages 2 and 5 years but by age 8 was below the 5th percentile. His head circumference was greater than 95th percentile at age 3 years and 25–50th percentiles at age 8 years. Developmentally, he remained globally delayed. His milestones, corrected for prematurity, were as follows: he sat at 9 months, began cruising at 14 months, and walking at 19 months. He began babbling around 8 months of age. At 17 months, he had 10 words. A formal developmental assessment was done at 22 months of age, and he was found to have a developmental quotient of 50. By 3.5 years of age, he was only using a few words and gestures, and at 5 years, he was nonverbal. He also had severe behavioral problems including extreme hyperactivity for which he was treated with clonidine and methylphenidate during early childhood. The behavioral problems began to abate around 4 years of age. Regarding medical treatment, the patient was evaluated for a bone marrow transplant but was determined to be ineligible due to his low developmental quotient. He was started on enzyme replacement therapy (ERT) for iduronidase deficiency at age 3 years. However, his severe hyperactivity often precluded therapy as he could not sit still during the infusions, and the intravenous access catheter infiltrated on numerous occasions. Given his mild somatic symptoms, the concurrent diagnosis of Sanfilippo syndrome, a lethal condition, as well as the difficulty his family had with his complex medical care, the decision was made with the family's participation and accord to discontinue ERT and to treat only those problems that would improve his quality of life. He was on ERT for a total of 3 years. 2.2. Case 2 The proband's sister is a 2-year-old female born of the same consanguineous union. The pregnancy was uncomplicated. The mother declined prenatal genetic testing. The patient was born full term via cesarian section with a birth weight of 7 pounds and 6 ounces. After birth, molecular genetic testing revealed the same homozygous mutations in the IDUA and SGSH genes as her brother. Thus, she was also diagnosed with combined Hurler syndrome and Sanfilippo syndrome type A. Her physical growth has not been impaired. All growth parameters at 2 years of age are above the 90th percentile. Her primary medical problem is recurrent otitis media. She has had more than 10 ear infections. Like her brother, she was also diagnosed with bilateral moderate to severe hearing loss. She has not developed corneal clouding yet. In terms of organ involvement, her liver was palpable 7 cm below the costal margin at age 2 years. An echocardiogram at the same age showed thickened mitral leaflets and mild to moderate regurgitation. Developmentally, she is mildly delayed, mainly in the language domain. Her motor milestones have been normal thus far. Given the conclusion to discontinue enzyme replacement therapy in her brother, the decision was made, again with the participation of
the patient's mother, not to initiate ERT unless she developed somatic symptoms that could be alleviated with treatment. 3. Discussion The mucopolysaccharidoses, as with most inborn errors of metabolism, are rare in the general population. Consanguinity may uncover recessive disorders due to the increased number of mutant alleles shared by a couple with a common ancestor. In the case of the two siblings in this report, both parents were carriers of MPS I and MPS III, which is an extraordinary circumstance. There are instances of individuals affected with more than one recessive condition, usually in the context of consanguinity (authors' personal experience). However, for an individual to carry aberrant alleles for two types of MPS is quite exceptional. Furthermore, the chance for such carrier parents to have two children affected with both disorders is 1/256. Phenotypically, the older brother had somatic manifestations of Hurler syndrome and neurobehavioral symptoms of Sanfilippo syndrome, although the lack of corneal clouding would seem to indicate a mild or attenuated form of Hurler syndrome. It is interesting to speculate whether a combination of MPS disorders would result in a more severe form of disease, perhaps with novel features. Given the clinical spectrum associated with varying degrees of residual enzyme activity, the ultimate phenotype would be difficult to predict. However, our patient's features appear to represent a true overlap of the two individual conditions. The decision to discontinue ERT in the older brother may be viewed by some as inappropriate or unethical. However, it is important to remember that this patient and his family are in a truly unique position. Firstly, he is affected with two conditions, both of which are progressive, and one of which is uniformly fatal. Treatment of one does not ameliorate the damage caused by the other. Even in patients with Hurler syndrome alone, ERT is not curative; it merely slows the progression of disease [4–6]. In a patient who has a second condition that is lethal, ERT may simply delay the inevitable outcome and prolong the period of unrelenting deterioration, during which time the patient's quality of life may be quite poor. Secondly, complex social problems permeated this family. The mother willingly renewed her relationship with her uncle, knowing the severity of her son's condition. She is a young, single mother and had tremendous difficulty with the complex medical care that her children required. Keeping appointments was a challenge, as were, ultimately, the weekly enzyme infusions. Lastly, and perhaps most importantly, the patient was not experiencing significant somatic symptoms. Therefore, the medical team, in conjunction with the patient's mother, chose to discontinue ERT. Likewise, ERT was not initiated for the younger sister. We have maintained a close relationship with the family and continue to follow both children at regular intervals. Such a unique family as theirs reminds us of the tragic nature of certain genetic conditions and teaches us to be mindful of both the science and art of medicine, the medical and psychosocial aspects of care. Acknowledgments We would firstly like to thank the patients and their mother for allowing us to participate in their care. We are also grateful to Dr. Ralph Lachman for his radiologic insights and expertise and to our colleagues at UCLA who have played a critical role in the ongoing care of these patients. References [1] P.J. Meikle, J.J. Hopwood, A.E. Clague, W.F. Carey, Prevalence of lysosomal storage disorders, JAMA 281 (1999) 249–254. [2] F. Baehner, C. Schmiedeskamp, F. Krummenauer, E. Miebach, M. Bajbouj, C. Whybra, A. Kohlschutter, C. Kampmann, M. Beck, Cumulative incidence rates of the mucopolysaccharidoses in Germany, J. Inherit. Metab. Dis. 28 (2005) 1011–1017. [3] Inborn Metabolic Diseases, in: J. Fernandes, J.M. Saudubray, G. van den Berghe, J.H. Walter (Eds.), 4th ed., Springer, 2006.
A. Sun et al. / Molecular Genetics and Metabolism 103 (2011) 135–137 [4] E.D. Kakkis, J. Muenzer, G.E. Tiller, L. Waber, J. Belmont, M. Passage, B. Izykowski, J. Phillips, R. Doroshow, I. Walot, R. Hoft, E.F. Neufeld, Enzyme-replacement therapy in mucopolysaccharidosis I, N. Engl. J. Med. 344 (3) (Jan 18 2001) 182–188. [5] J.E. Wraith, L.A. Clarke, M. Beck, E.H. Kolodny, G.M. Pastores, J. Muenzer, D.M. Rapoport, K.I. Berger, S.J. Swiedler, E.D. Kakkis, T. Braakman, E. Chadbourne, K. Walton-Bowen,
137
G.F. Cox, Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase), Pediatrics 144 (5) (May 2004) 581–588. [6] J. Muenzer, J.E. Wraith, L.A. Clarke, Mucopolysaccharidosis I: management and treatment guidelines, Pediatrics 123 (1) (Jan 2009) 19–29.
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y m g m e
Combined Hurler and Sanfilippo syndrome in a sibling pair Angela Sun a,⁎, John J. Hopwood b, Jerry Thompson c, Stephen D. Cederbaum d a
UCLA Intercampus Medical Genetics Training Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA Lysosomal Diseases Research Unit, A Research Centre of SA Pathology, Women's and Children's Hospital, North Adelaide, SA, Australia c Department of Genetics, University of Alabama at Birmingham, AL, USA d Departments of Psychiatry, Pediatrics and Human Genetics, UCLA Center for the Health Sciences, Los Angeles, CA, USA b
a r t i c l e
i n f o
Article history: Received 28 December 2010 Received in revised form 16 February 2011 Accepted 16 February 2011 Available online 22 February 2011 Keywords: Hurler syndrome Sanfilippo syndrome Enzyme replacement therapy Psychosocial issues
a b s t r a c t The mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by defects in the enzymes involved in the degradation of glycosaminoglycans. Hurler syndrome (MPS I) and Sanfilippo syndrome (MPS III) are among the more common diseases in the group, each occurring with an incidence of approximately 1 in 100,000. We present a case of siblings, born of a consanguineous union, affected with both MPS I and MPS IIIa. The diagnoses were confirmed with fibroblast enzyme assays and sequence analysis of the genes, which identified homozygous mutations in IDUA and SGSH. We discuss their clinical features and course and examine the psychosocial aspects of their case, specifically, the decision-making process that the medical team and family faced regarding treatment with enzyme replacement therapy. © 2011 Elsevier Inc. All rights reserved.
1. Introduction The mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by defects in the enzymes involved in the degradation of glycosaminoglycans. Hurler syndrome and Sanfilippo syndrome are among the more common diseases in the group, each occurring with an incidence of approximately 1 in 100,000 [1,2]. Individuals with Hurler syndrome or MPS I have deficiency of the enzyme alpha-L-iduronidase and present with developmental delay, coarse facial features, upper airway obstruction, respiratory infections, cardiac disease, and hepatosplenomegaly [3]. There are four subtypes of Sanfilippo syndrome or MPS III, all of which are caused by deficiency of enzymes involved in the breakdown of heparan sulfate. Patients with MPS III typically manifest with neurologic rather than somatic symptoms such as severe behavioral problems, poor sleep, and progressive neurological deterioration [3]. We present a case of siblings affected with both MPS I and MPS III and discuss their clinical features and course. 2. Case reports 2.1. Case 1 The proband is an 8-year-old male of Mexican origin who was the product of an uncle–niece union. He was born at 32 weeks gestational age to a 20-year old gravida 1 para 1 mother via normal spontaneous vaginal delivery. His birth weight was 3 pounds and 12 ounces. During
⁎ Corresponding author at: 8700 Beverly Blvd, PACT 4, Los Angeles, CA 90048, USA. E-mail address: [email protected] (A. Sun). 1096-7192/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2011.02.011
the first year of life, he was noted to have developmental delay and coarse facial features. He was clinically diagnosed with Hurler syndrome at age 1.5 years. Urinary quantitation of glycosaminoglycans showed 127 mg/g creatinine of uronic acid by the orcinol reaction (nl. 10.7 ± 8.0) and 449 mg/g creatinine by the carbazole reaction (nl. 16.9 ± 9.9), giving a carbazole to orcinol ratio of almost 3, which is indicative of excess heparan sulfate as compared with dermatan sulfate. The electrophoresis which revealed a strong band of heparan sulfate and slightly less chondroitin sulfate was confirmatory of this conclusion. Nsulfated hexosamine was 126 mg/g creatinine (nl. 15.8 ± 12). Enzyme analysis on fibroblasts showed 10% residual alpha-L-iduronidase activity and no detectable activity for heparan N-sulfatase. Molecular genetic testing revealed a homozygous c.923TN C (L308P) mutation in the IDUA gene, which has not been previously reported, and a homozygous c.268G N A (G90R) mutation in the SGSH gene, a known pathogenic variant. Thus, he was diagnosed with combined Hurler syndrome and Sanfilippo syndrome type A. During early childhood, the patient had significant problems with gastroesophageal reflux due to a hiatal hernia. He underwent a Nissen fundoplication and a later revision. He also had an umbilical hernia repair. He had multiple hospital admissions for pneumonia and asthma exacerbations. He also had recurrent otitis media, and pressure equalization tubes were placed on multiple occasions. He developed bilateral moderate to severe hearing loss and was prescribed hearing aids. He had a tonsillectomy and adenoidectomy at age 5 years, after which his breathing improved. An abdominal ultrasound at 5 years of age showed an enlarged liver measuring 14.1 cm. His spleen remained normal in size. An echocardiogram at 17 months of age showed mild concentric left ventricular hypertrophy, and at 4 years of age showed a minimal septal bulge into the
136
A. Sun et al. / Molecular Genetics and Metabolism 103 (2011) 135–137
left ventricular outflow tract and otherwise normal cardiac anatomy and function. An MRI of the brain at age 2 years was normal. He reportedly had a normal ophthalmologic examination at 3 years of age, and at age 8 has not developed corneal clouding. The patient had mild orthopedic complications. A skeletal survey at 2 years of age showed early signs of dysostosis multiplex including a J-shaped sella, short and slightly expanded metacarpal bones with thin cortices, and a narrow iliac base with rounded iliac wings. A chest X-ray at age 7 revealed paddle-shaped ribs and short, thickened clavicles. At age 4 years, he began to have increasing joint stiffness, most notably in his ankles, which resulted in toe-walking. He underwent a heel cord release when he was 6 years old. With age, he developed contractures at the knees for which he was prescribed braces. He began losing his ability to ambulate between ages 6 and 7 years. In terms of physical growth, the patient's height remained in the 10–50th percentiles up to age 6, after which his linear growth began to fall off. His weight was at or above the 90th percentile between ages 2 and 5 years but by age 8 was below the 5th percentile. His head circumference was greater than 95th percentile at age 3 years and 25–50th percentiles at age 8 years. Developmentally, he remained globally delayed. His milestones, corrected for prematurity, were as follows: he sat at 9 months, began cruising at 14 months, and walking at 19 months. He began babbling around 8 months of age. At 17 months, he had 10 words. A formal developmental assessment was done at 22 months of age, and he was found to have a developmental quotient of 50. By 3.5 years of age, he was only using a few words and gestures, and at 5 years, he was nonverbal. He also had severe behavioral problems including extreme hyperactivity for which he was treated with clonidine and methylphenidate during early childhood. The behavioral problems began to abate around 4 years of age. Regarding medical treatment, the patient was evaluated for a bone marrow transplant but was determined to be ineligible due to his low developmental quotient. He was started on enzyme replacement therapy (ERT) for iduronidase deficiency at age 3 years. However, his severe hyperactivity often precluded therapy as he could not sit still during the infusions, and the intravenous access catheter infiltrated on numerous occasions. Given his mild somatic symptoms, the concurrent diagnosis of Sanfilippo syndrome, a lethal condition, as well as the difficulty his family had with his complex medical care, the decision was made with the family's participation and accord to discontinue ERT and to treat only those problems that would improve his quality of life. He was on ERT for a total of 3 years. 2.2. Case 2 The proband's sister is a 2-year-old female born of the same consanguineous union. The pregnancy was uncomplicated. The mother declined prenatal genetic testing. The patient was born full term via cesarian section with a birth weight of 7 pounds and 6 ounces. After birth, molecular genetic testing revealed the same homozygous mutations in the IDUA and SGSH genes as her brother. Thus, she was also diagnosed with combined Hurler syndrome and Sanfilippo syndrome type A. Her physical growth has not been impaired. All growth parameters at 2 years of age are above the 90th percentile. Her primary medical problem is recurrent otitis media. She has had more than 10 ear infections. Like her brother, she was also diagnosed with bilateral moderate to severe hearing loss. She has not developed corneal clouding yet. In terms of organ involvement, her liver was palpable 7 cm below the costal margin at age 2 years. An echocardiogram at the same age showed thickened mitral leaflets and mild to moderate regurgitation. Developmentally, she is mildly delayed, mainly in the language domain. Her motor milestones have been normal thus far. Given the conclusion to discontinue enzyme replacement therapy in her brother, the decision was made, again with the participation of
the patient's mother, not to initiate ERT unless she developed somatic symptoms that could be alleviated with treatment. 3. Discussion The mucopolysaccharidoses, as with most inborn errors of metabolism, are rare in the general population. Consanguinity may uncover recessive disorders due to the increased number of mutant alleles shared by a couple with a common ancestor. In the case of the two siblings in this report, both parents were carriers of MPS I and MPS III, which is an extraordinary circumstance. There are instances of individuals affected with more than one recessive condition, usually in the context of consanguinity (authors' personal experience). However, for an individual to carry aberrant alleles for two types of MPS is quite exceptional. Furthermore, the chance for such carrier parents to have two children affected with both disorders is 1/256. Phenotypically, the older brother had somatic manifestations of Hurler syndrome and neurobehavioral symptoms of Sanfilippo syndrome, although the lack of corneal clouding would seem to indicate a mild or attenuated form of Hurler syndrome. It is interesting to speculate whether a combination of MPS disorders would result in a more severe form of disease, perhaps with novel features. Given the clinical spectrum associated with varying degrees of residual enzyme activity, the ultimate phenotype would be difficult to predict. However, our patient's features appear to represent a true overlap of the two individual conditions. The decision to discontinue ERT in the older brother may be viewed by some as inappropriate or unethical. However, it is important to remember that this patient and his family are in a truly unique position. Firstly, he is affected with two conditions, both of which are progressive, and one of which is uniformly fatal. Treatment of one does not ameliorate the damage caused by the other. Even in patients with Hurler syndrome alone, ERT is not curative; it merely slows the progression of disease [4–6]. In a patient who has a second condition that is lethal, ERT may simply delay the inevitable outcome and prolong the period of unrelenting deterioration, during which time the patient's quality of life may be quite poor. Secondly, complex social problems permeated this family. The mother willingly renewed her relationship with her uncle, knowing the severity of her son's condition. She is a young, single mother and had tremendous difficulty with the complex medical care that her children required. Keeping appointments was a challenge, as were, ultimately, the weekly enzyme infusions. Lastly, and perhaps most importantly, the patient was not experiencing significant somatic symptoms. Therefore, the medical team, in conjunction with the patient's mother, chose to discontinue ERT. Likewise, ERT was not initiated for the younger sister. We have maintained a close relationship with the family and continue to follow both children at regular intervals. Such a unique family as theirs reminds us of the tragic nature of certain genetic conditions and teaches us to be mindful of both the science and art of medicine, the medical and psychosocial aspects of care. Acknowledgments We would firstly like to thank the patients and their mother for allowing us to participate in their care. We are also grateful to Dr. Ralph Lachman for his radiologic insights and expertise and to our colleagues at UCLA who have played a critical role in the ongoing care of these patients. References [1] P.J. Meikle, J.J. Hopwood, A.E. Clague, W.F. Carey, Prevalence of lysosomal storage disorders, JAMA 281 (1999) 249–254. [2] F. Baehner, C. Schmiedeskamp, F. Krummenauer, E. Miebach, M. Bajbouj, C. Whybra, A. Kohlschutter, C. Kampmann, M. Beck, Cumulative incidence rates of the mucopolysaccharidoses in Germany, J. Inherit. Metab. Dis. 28 (2005) 1011–1017. [3] Inborn Metabolic Diseases, in: J. Fernandes, J.M. Saudubray, G. van den Berghe, J.H. Walter (Eds.), 4th ed., Springer, 2006.
A. Sun et al. / Molecular Genetics and Metabolism 103 (2011) 135–137 [4] E.D. Kakkis, J. Muenzer, G.E. Tiller, L. Waber, J. Belmont, M. Passage, B. Izykowski, J. Phillips, R. Doroshow, I. Walot, R. Hoft, E.F. Neufeld, Enzyme-replacement therapy in mucopolysaccharidosis I, N. Engl. J. Med. 344 (3) (Jan 18 2001) 182–188. [5] J.E. Wraith, L.A. Clarke, M. Beck, E.H. Kolodny, G.M. Pastores, J. Muenzer, D.M. Rapoport, K.I. Berger, S.J. Swiedler, E.D. Kakkis, T. Braakman, E. Chadbourne, K. Walton-Bowen,
137
G.F. Cox, Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase), Pediatrics 144 (5) (May 2004) 581–588. [6] J. Muenzer, J.E. Wraith, L.A. Clarke, Mucopolysaccharidosis I: management and treatment guidelines, Pediatrics 123 (1) (Jan 2009) 19–29.