Clinical, biochemical and molecular characteristics of Filipino patients with mucopolysaccharidosis type II - Hunter syndrome

Abstract

Background: Mucopolysaccharidosis type II, an X-linked recessive disorder is the most common lysosomal storage disease detected among Filipinos. This is a case series involving 23 male Filipino patients confirmed to have Hunter syndrome. The clinical and biochemical characteristics were obtained and mutation testing of the IDS gene was done on the probands and their female relatives.

Results: The mean age of the patients was 11.28 (SD 4.10) years with an average symptom onset at 1.2 (SD 1.4) years. The mean age at biochemical diagnosis was 8 (SD 3.2) years. The early clinical characteristics were developmental delay, joint stiffness, coarse facies, recurrent respiratory tract infections, abdominal distention and hernia. Majority of the patients had joint contractures, severe intellectual disability, error of refraction, hearing loss and valvular regurgitation on subspecialists' evaluation. The mean GAG concentration was 506.5 mg (SD 191.3)/grams creatinine while the mean plasma iduronate-2-sulfatase activity was 0.86 (SD 0.79) nmol/mg plasma/4 h. Fourteen (14) mutations were found: 6 missense (42.9%), 4 nonsense (28.6%), 2 frameshift (14.3%), 1 exon skipping at the cDNA level (7.1%), and 1 gross insertion (7.1%). Six (6) novel mutations were observed (43%): p.C422F, p.P86Rfs*44, p.Q121*, p.L209Wfs*4, p.T409R, and c.1461_1462insN[710].

Conclusion: The age at diagnosis in this series was much delayed and majority of the patients presented with severe neurologic impairment. The results of the biochemical tests did not contribute to the phenotypic classification of patients. The effects of the mutations were consistent with the severe phenotype seen in the majority of the patients.

Keywords: Glycosaminoglycans; Hunter syndrome; Iduronate-2-sulfatase gene; Lysosomal storage disease; Mucopolysaccharidosis type II.

Fig. 1

Scatter plot of age and weight. Patients gained weight as they grew older

Fig. 2

Scatter plot of age and height. Patients’ heights flattened as they grew older

Fig. 3

Scatter plot of age and head circumference. Patients’ head circumference grew bigger as they got older

Fig. 4

Reported early clinical symptoms among Filipino patients with Hunter syndrome. The most common symptoms were developmental delay, followed by joint stiffness, coarse facies, recurrent upper respiratory tract infections, abdominal distention and hernia and recurrent ear infections

Fig. 5

Clinical characteristics of MPS II patients noted during subspecialists’ evaluations. More than half of the patients had intellectual disability, joint stiffness and error of refraction

Fig. 6

Distribution of Iduronate-2-sulfatase (in nmol/mg/plasma/4 h) levels among 23 patients with Hunter syndrome. The distribution of plasma iduronate 2 sulfatase activity was skewed indicating that regardless of the phenotype, most had levels of less than 1 nmol/mg/plasma/4 h

Fig. 7

Gel image of carrier testing for exon 8 skipping at cDNA level through gap PCR; 1:100-bp DNA ladder, 2: patient, 3: patient’s mother, 4–8: other female family members, 9: healthy female control, 10: negative control