Background: Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is an X-linked multisystem disorder resulting from the defective activity of the enzyme iduronate-2-sulfatase (IDS). Genetic testing is crucial in clarifying and diagnosing different types of MPS diseases. In this paper we report a novel IDS nonsense mutation resulting in MPS II in several patients from a Chinese family. Methods: IDS enzyme activity, polymerase chain reaction, and DNA sequencing were performed to confirm the diagnosis of MPS II. Results: Three patients had no detectable IDS activity. Two genetic tests revealed a novel IDS nonsense mutation (c.1030G&gt;T, p.E344X) inherited from their mothers. The nonsense mutation shortened the peptide chain from 550 to 344 amino acids, which is believed to be a disease-causing mutation. Conclusions: MPS II is inherited in an X-linked manner. The risk to sibs depends on the carrier status of the mother. Genetic testing is necessary to identify disease-causing mutation. With this information, carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk become possible. World J Pediatr 2012;8(3):281-28

Ju J

Li Xy

Li-Ping Zou

Shi Xy

Yang Xf

Zou Lp

CiteSeerX

281
IDS mutation in a Chinese MPS II patient
C
ase report
World J Pediatr, Vol 8 No 3 . August 15, 2012 .  www.wjpch.com
Author Affiliations: Department of Pediatrics, Chinese PLA General 
Hospital, 28 Fuxing Road, Beijing 100853, China (Li XY, Shi XY, Ju J, 
Yang XF, Zou LP); Department of Pediatrics, First Affiliated Hospital of 
Chinese PLA General Hospital, 51 Fucheng Street, Beijing 100037, China 
(Hu XH)
Corresponding Author: Li-Ping Zou, Department of Pediatrics, Chinese 
PLA General Hospital, 28 Fuxing Road, Beijing 100853, China (Tel: +86 
10 55499016; Fax: +86 10 55499016; Email: zouliping21@hotmail.com)
doi: 10.1007/s12519-012-0357-1
©Children's Hospital, Zhejiang University School of Medicine, China and 
Springer-Verlag Berlin Heidelberg 2012. All rights reserved.
Background: Mucopolysaccharidosis type II (MPS 
II; also known as Hunter syndrome) is an X-linked 
multisystem disorder resulting from the defective 
activity of the enzyme iduronate-2-sulfatase (IDS). 
Genetic testing is crucial in clarifying and diagnosing 
different types of MPS diseases. In this paper we report 
a novel IDS nonsense mutation resulting in MPS II in 
several patients from a Chinese family.
Methods: IDS enzyme activity, polymerase chain 
reaction, and DNA sequencing were performed to 
confirm the diagnosis of MPS II.
Results: Three patients had no detectable IDS 
activity. Two genetic tests revealed a novel IDS nonsense 
mutation (c.1030G>T, p.E344X) inherited from their 
mothers. The nonsense mutation shortened the peptide 
chain from 550 to 344 amino acids, which is believed to 
be a disease-causing mutation.
Conclusions: MPS II is inherited in an X-linked 
manner. The risk to sibs depends on the carrier status 
of the mother. Genetic testing is necessary to identify 
disease-causing mutation. With this information, carrier 
testing for at-risk female relatives and prenatal testing 
for pregnancies at increased risk become possible.
World J Pediatr 2012;8(3):281-283
Key words: iduronate 2-sulfatase gene;
                   mucopolysaccharidosis II;
                   mutation
Introduction
Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is an X-linked multisystem disorder caused by a deficiency 
in IDS activity. The disorder is characterized by 
glycosaminoglycan (GAG) accumulation. MPS II has 
an incidence of approximately 0.31 to 0.71 per 100 000 
live births.[1] The vast majority of affected individuals 
are male, and to date, very few female patients with 
MPS II have been reported. Disease phenotypes in most 
females with MPS II are due to the inherited IDS gene 
mutation from the mother with preferential inactivation 
of the non-mutant paternal alleles.[2] The clinical 
spectrum of MPS II varies significantly and includes 
mild, intermediate, and severe variants according to the 
age of onset, disease severity, and rate of progression. 
Urine GAGs, skeletal survey, and IDS enzyme activity 
facilitate the diagnosis of MPS II. However, genetic 
testing for IDS is necessary for the male patients who 
present unusual phenotypes or phenotypes that do 
not match the results of GAG tests. Furthermore, the 
identification of IDS mutation is important for genetic 
counseling and prenatal diagnosis. In the current report 
we present three male patients (all of whom are cousins) 
with MPS II resulting from a nonsense IDS mutation.
Case reports
Clinical information
Proband: A 4-year-old boy who had been experiencing 
abdominal distension and diarrhea for one month was 
brought to our clinic. Physical examination showed 
that his liver was 10 cm below the right costal margin 
in the mid-clavicular line, with a firm, sharp margin. 
His spleen was 8 cm below the left costal margin in 
the midclavicular line. He suffered from a coarse face, 
including prominent supraorbital ridges, a broad nose 
and nasal bridge, large rounded cheeks, thick lips, and 
such features as a short neck and small stubby fingers. 
He was born normally to non-consanguineous parents. 
The development of his psychomotor and speech was 
delayed, and he experienced an increased frequency of 
recurrent respiratory infections. Magnetic resonance 
A novel iduronate 2-sulfatase mutation in a Chinese family 
with mucopolysaccharidosis type II
Xiao-Yan Li, Xiu-Yu Shi, Jun Ju, Xiao-Hong Hu, Xiao-Fan Yang, Li-Ping Zou
Beijing, China
282
World Journal of Pediatrics
C
ase report
World J Pediatr, Vol 8 No 3 . August 15, 2012 . www.wjpch.com
imaging revealed encephalatrophy.
Patient 2: A 5-year-old boy, an older cousin of 
the proband, was brought to our clinic owing to a 
similar coarsening of the facial features. Patient 2 also 
suffered from hepatosplenomegaly and navel hernia. 
His developmental progress was slow. Anteroposterior 
and lateral X-rays of the chest showed wide ribs with 
tapered posterior ends and a paddle appearance.
Patient 3: A 1 year and 4 months old boy, a young 
cousin of the proband and patient 2. He did not have 
the typical coarsening of facial features. Physical 
examination showed that his head circumference was 48 
cm. In addition, his ribs had a similar outer border. His 
liver and spleen were only slightly enlarged, and there 
was a large piece of cyan birthmark on his back. He had 
inguinal hernia. The boy had febrile convulsions twice 
when he was just nine months old. He was born by 
uterine-incision delivery because of oligohydramnios. 
However, this patient did not have a history of poor 
oxygen or asphyxia. To date, his growth development is 
normal for his age.
IDS activity and gene testing
Enzyme assay for iduronate sulfatase showed that the 
three patients had no detectable IDS activity. Genetic 
tests were performed on the proband and patient 2. The 
results showed a novel nonsense mutation (c.1030G>T, 
p.E344X) inherited from their mothers (Fig.). Mutation 
E344X caused the elongation of the amino acid chain to 
G A A C T A G G G T G G G C T C T A G G T G A A C A T G G A G A A T G G G C C A A A T A C A G C A A T T T T G A T
G A A C T A G G G T G G G C T C T A G G T G A A C A T G G A T A A T G G G C C A A A T A C A G C A A T T T T G A T
A A C T A G G G T G G G C T C T A G G T G A A C A T G G A T A A T G G G C C A A A T A C A G C A A T T T T G A T G
B
b
a
c
A
I
II
III
+/M +/M
MM
?
Fig. Pedigrees and genetic analysis of patients with IDS mutations. 
A: Pedigrees of affected family with novel IDS mutation (proband 
indicated by arrow); shaded square indicates affected individuals; +/M: 
individual carrying heterozygous IDS mutation; M: male individual 
carrying IDS mutation. B: Chromatograms of IDS mutations, in 
comparison with normal sequence and heterozygous IDS mutation 
carrier. Arrows indicate the occurrence of mutations. a: control; b: 
mother; c: patient.
stop at position 344; thus, the mutation was believed to 
be disease causing. Although genetic analysis was not 
performed on patient 3, it was assumed that he might 
have had the same mutation. The other family members 
refused to undergo the genetic analysis. Thus, other 
carriers and patients may exist within the family.
Discussion
MPS II, inherited in an X-linked recessive manner, is a 
lysosomal storage disorder caused by IDS deficiency. 
In the present study, we present three patients who 
are cousins and have similar symptoms, including 
distinctive facial appearance, hepatosplenomegaly, 
moderate mental retardation, recurrent respiratory 
infections, and skeletal deformities. The clinical 
spectrum of MPS II varies greatly, and involves the 
central nervous system (CNS). The severe form of 
the disorder is characterized by progressive mental 
retardation, physical disabili ty,  severe airway 
obstruction, skeletal deformities, and cardiomyopathy 
resulting in death in the first or second decade of life. 
The CNS of patients with a mild form of MPS II is 
minimally affected or not at all. However, the effect 
of GAG accumulation on the other systems may be 
similar to that in the severe form. The gold criterion 
for diagnosis of MPS II is detecting activity of IDS 
enzyme, while gene testing is essential, especially 
in young patients and those who present atypical 
phenotype or one that does not match the results of 
GAG testing.
The human IDS gene (MIM 300823) is located in 
Xq28 and contains nine exons spanning approximately 
24 kb chromosome regions. IDS is the only gene 
associated with MPS II, thus playing a pivotal role 
in its diagnosis. Using a direct sequencing method, 
we identified an IDS nonsense mutation c.1030G>T, 
p.E344X resulting in IDS deficiency in the three 
patients. A search in the Human GeneMutation 
Database (HGMD, http://www.hgmd.org/) confirmed 
this nonsense mutation to be a novel case first 
reported in the present study. To date, more than 350 
IDS mutations have been found, including exonic 
point mutations comprising half mutations, followed 
by exonic and whole-gene deletions,  complex 
rearrangements, and gross insertions/duplications.
In a large collection of Chinese patients with MPS 
II, Zhang et al[3] identified many different mutations, 
of which the most frequent mutations are also exonic 
point mutations. In addition, a synonymous mutation 
c.879G>A (p.Gln293Gln) was identified in a female 
patient with MPS II, which resulted in loss of the 
original splicing site, activated a cryptic splicing site 
283
IDS mutation in a Chinese MPS II patient
C
ase report
World J Pediatr, Vol 8 No 3 . August 15, 2012 .  www.wjpch.com
upstream, leading to a 28 bp deletion and a premature 
termination at p.Tyr285GlufsX47. Together with 
concurrent skewed X-inactivation this synonymous 
mutation (p.Gln293Gln) was believed to facilitate the 
development of MPS II in this girl. Otherwise, IDS 
mutations from this largest cohort of Chinese patients 
are frequently located in exon 9, next to exon 2, and 
against exon 3. These results, however, are different 
from those of foreign studies, indicating that the IDS 
gene has high genetic heterogeneity, and the mutation 
patterns of patients from different races, nations and 
areas are diversified.
In general, the IDS genotype correlates with the 
clinical phenotype. Boys with a complete absence of 
functional enzymes owing to gross IDS gene changes, 
for example, large deletions and gene-pseudogene 
rearrangements, invariably manifest severe CNS 
symptoms.[4] Regarding IDS point mutations, a 
significant genotype-phenotype correlation has yet to be 
established. In the present study, the nonsense mutation 
c.1030G>T, p.E344X resulted in an intermediate 
phenotype. Missense mutations are associated with 
the severe, intermediate, or attenuated phenotype.[5] 
Furthermore, previous studies have reported two siblings 
with the same IDS mutations, in which one brother 
displays severe symptoms, whereas the other presents 
attenuated symptoms.[6,7] Other factors are more likely to 
modify the IDS effects on the clinical presentation.
Treatment of MPS II is symptomatic and palliative, 
based on the coordination of diverse medical specialties. 
Although the treatment for MPS II with hematopoietic 
stem cell transplantation has been proposed in the 
1980s, the results are not considered satisfactory.[8] 
In 2006, enzyme replacement therapy (Elaprase) was 
approved for clinical use for MPS II.[9,10] Most of the 
clinical trials studied the effect of Elaprase on patients 
with relatively attenuated symptoms.[11] However, no 
information on the outcome of Elaprase on individuals 
with severe CNS disease is currently available. In 
addition, the high price of Elaprase limits its use in 
China. Thus, MPS II remains an important social and 
economic concern.
In summary, we found a novel IDS nonsense 
mutation in two related patients who were cousins. 
Identifying IDS mutations is important for the 
genetic counseling and prenatal diagnosis in affected 
families. Genetic counseling can provide families with 
information about reproductive risks. Thus, this method 
can be used to make a prenatal diagnosis for pregnant 
women at high risk of MPS II, and it can also contribute 
to the prevention of MPS II occurrence.
Funding: None.
Ethical approval: Not needed.
Competing interest: The authors declare that they have no 
competing interests.
Contributors: Li XY, Shi XY and Zou LP have done all the work 
in the laboratory and participated in drafting the manuscript. Ju J, 
Hu XH and Yang XF were responsible for acquisition of clinical 
data. All authors have read and approved the final manuscript. Li 
XY and Shi XY contributed equally to the paper.
References
1 Baehner F, Schmiedeskamp C, Krummenauer F, Miebach E, 
Bajbouj M, Whybra C, et al. Cumulative incidence rates of 
the mucopolysaccharidoses in Germany. J Inherit Metab Dis 
2005;28:1011-1017.
2 Tuschl K, Gal A, Paschke E, Kircher S, Bodamer OA. 
Mucopolysaccharidosis type II in females: case report and 
review of literature. Pediatr Neurol 2005;32:270-272.
3 Zhang H, Li J, Zhang X, Wang Y, Qiu W, Ye J, et al. Analysis of 
the IDS gene in 38 patients with Hunter syndrome: the c.879G>A 
(p.Gln293Gln) synonymous variation in a female create exonic 
splicing. PLoS One 2011;6:e22951.
4 Wraith JE, Beck M, Giugliani R, Clarke J, Martin R, Muenzer 
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5 Muenzer J, Beck M, Eng CM, Escolar ML, Giugliani R, Guffon 
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6 Yatziv S, Erickson RP, Epstein CJ. Mild and severe Hunter 
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7 Martin R, Beck M, Eng C, Giugliani R, Harmatz P, Munoz V, 
et al. Recognition and diagnosis of mucopolysaccharidosis II 
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8 Wraith JE, Scarpa M, Beck M, Bodamer OA, De Meirleir 
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9 First treatment for Hunter syndrome. FDA Consum 2006;40:5.
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11 Muenzer J, Wraith JE, Beck M, Giugliani R, Harmatz P, Eng 
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Received February 3, 2012
Accepted after revision March 21, 2012


IDS mutation in a Chinese MPS II patient Case report

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IDS mutation in a Chinese MPS II patient Case report

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