Sung-Yoon Cho

High prevalence of carpal tunnel syndrome in children with mucopolysaccharidosis type II (Hunter syndrome)

Although carpal tunnel syndrome (CTS) is the most common compressive neuropathy seen in the upper extremity of adults, it is rarely seen in children. Several reports have shown that mucopolysaccharidosis type II (Hunter syndrome), a rare genetic disorder, is one of the causes of CTS in children. Usual symptoms of CTS are pain, weakness, and paresthesias in the hand and digits. However, the diagnosis of CTS in Hunter syndrome is often delayed or unrecognized because of atypical symptoms and cognitive impairment. Here, we report the prevalence, clinical manifestation, and nerve conduction profiles of CTS in 45 Hunter syndrome patients. The mean age of the study participants was 117.1 (74.9) months (range: 4–408 months); all patients were male. Forty‐three (96.0%) of the 45 patients with Hunter syndrome had CTS. Bilateral CTS was observed in all patients; 73 (82.0%) of the patients hands had severe degree of CTS. Intriguingly, in contrast with other nerve velocities, decreases in forearm conduction velocities of the median nerve were observed in 28 (31.5%) of 89 hands with CTS. There was a significant difference in age (Pu2009<u20090.001) between hands with normal, mild, moderate, and severe grades of CTS. The compound muscle action potential and sensory nerve action potential amplitudes of the median nerves decreased with age (CMAP, ru2009=u2009−0.526, Pu2009<u20090.001; SNAP, ru2009=u2009−0.564, Pu2009<u20090.001). Early recognition and intervention to ameliorate the symptoms of CTS are important in improving the quality of life of Hunter syndrome patients.

IgE-mediated anaphylaxis and allergic reactions to idursulfase in patients with Hunter syndrome

Enzyme replacement therapy (ERT) with recombinant human idursulfase is effective for the treatment of Hunter syndrome, mucopolysaccharidosis (MPS) type II. However, various adverse events can occur by the infusion of idursulfase. The purpose was to evaluate the occurrence of infusion‐related allergic reactions, including anaphylaxis, to idursulfase in patients with MPS II receiving ERT and to elucidate its possible mechanism.

A polymorphism in the growth hormone receptor is associated with height in children with Prader-Willi syndrome.

The exon‐3 deletion polymorphism (d3, Database of Genomic Variants ID: Variation_64191) in the growth hormone receptor (GHR) gene is associated with increased growth response to growth hormone (GH) therapy in GH‐deficient patients. However, an association of the GHR genotype with height has not yet been reported in Prader–Willi syndrome (PWS). The aim of this study was to assess the association of GHR alleles with height before starting GH therapy in patients with PWS. Seventy‐four patients with PWS were genotyped and their medical records were retrospectively reviewed (45 males and 29 females, median age 8.7 years). One hundred normal controls, with known final height, were also genotyped. The GH‐exon 3 locus was genotyped using a PCR multiplex assay. The distribution of alleles in the patients with PWS was not different from controls [(fl/fl nu2009=u200953 (72%), fl/d3 nu2009=u200921 (28%)) in PWS vs. (fl/fl nu2009=u200972(72%), fl/d3 nu2009=u200926(26%), and d3/d3 nu2009=u20092(2%)]. However, patients with PWS carrying a d3 allele had significantly greater height standard deviation scores (SDS) (Pu2009=u20090.025) and higher insulin‐like growth factor I (IGF‐I) level (Pu2009=u20090.041), although the age at the start of GH therapy, weight, BMI, and body fat were not different. The d3 allele was associated with height and IGF‐I levels before GH therapy and suggests that even before GH therapy, d3 allele may influence height through GH secretion.

Retrospective analysis of the clinical manifestations and survival of Korean patients with mucopolysaccharidosis type II: Emphasis on the cardiovascular complication and mortality cases†‡§

Hunter syndrome (mucopolysaccharidosis II, MPS II) is a rare, X‐linked disorder of glycosaminoglycan (GAG) catabolism caused by a deficiency in the activity of the lysosomal enzyme, iduronate‐2‐sulfatase (I2S). In this study, the medical records of 75 Korean patients with Hunter syndrome (74 males, 1 female) were retrospectively reviewed to investigate the frequency of organ involvement and survival at a single center. The three most common symptoms of organ involvement were hepatosplenomegaly (99%), facial dysmorphism (97%), and frequent otitis media (91%). Cardiovascular involvement was also common including valvular abnormalities (89%), left ventricular hypertrophy (68%), and hypertension (30%). The 19 patients who died had a median age of 16.8 years at the time of death. Four of them died within 1 year of the start of enzyme replacement therapy; autopsy showed myocardial infarction with severe coronary artery disease in one patient. Two other patients died due to pneumonia and sleep apnea. In one case, the cause of death was not investigated. The high incidence of hypertension, and the presence of valvular heart disease indicates that close cardiac monitoring is mandatory in all patients with Hunter syndrome, especially relatively older patients even if they are being treated with enzyme replacement therapy.

Auditory characteristics and therapeutic effects of enzyme replacement in mouse model of the mucopolysaccharidosis (MPS) II

Mucopolysaccharidosis (MPS) II is an X‐linked metabolic disorder caused by dysfunction of iduronate‐2‐sulfatase (I2S). This abnormality causes the progressive accumulation of incompletely degraded glycosaminoglycans (GAGs) in the lysosomes. The auditory characteristics of MPS II in mouse models have not been reported. In this study, we evaluated the auditory characteristics of the MPS II in IDS knock‐out (IDS‐KO) mice. In addition, the effect of enzyme replacement therapy (ERT) on hearing was studied. The IDS‐KO mice had normal histology of the cochlea and retained good hearing at 7 weeks of age. However, at 17 weeks of age, the hearing thresholds of the IDS‐KO mice were elevated and exudates were found in the middle ear. The hearing thresholds of the enzyme‐treated IDS‐KO (IDS‐ERT) mice were similar to the wild‐type (WT) mice at 17 weeks. Moreover, the microstructure of the inner ear was similar to the IDS‐KO by transmission electron microscopy. The histology findings indicated that the microstructure of the inner ear was similar in comparisons between IDS‐KO and IDS‐ERT mice, even after 10 weeks of treatment. However, the hearing deficits in the MPS II mouse model can be prevented if ERT is started before the onset of hearing impairment.

The metabolic syndrome and body composition in childhood cancer survivors

Purpose Long-term survivors of childhood cancer appear to have an increased risk for the metabolic syndrome, subsequent type 2 diabetes and cardiovascular disease in adulthood compared to healthy children. The purpose of this study was to investigate the frequency of the metabolic syndrome and associated factors in childhood cancer survivors at a single center in Korea. Methods We performed a retrospective review of medical records of 98 childhood cancer survivors who were diagnosed and completed anticancer treatment at Samsung Medical Center, Seoul, Korea between Jan. 1996 and Dec. 2007. Parameters of metabolic syndrome were evaluated between Jan. 2008 and Dec. 2009. Clinical and biochemical findings including body fat percentage were analyzed. Results A total of 19 (19.4%) patients had the metabolic syndrome. The median body fat percentage was 31.5%. The body mass index and waist circumference were positively correlated with the cranial irradiation dose (r=0.38, P<0.001 and r=0.44, P<0.00, respectively). Sixty-one (62.2%) patients had at least one abnormal lipid value. The triglyceride showed significant positive correlation with the body fat percentage (r=0.26, P=0.03). The high density lipoprotein cholesterol showed significant negative correlation with the percent body fat (r=-0.26, P=0.03). Conclusion Childhood cancer survivors should have thorough metabolic evaluation including measurement of body fat percentage even if they are not obese. A better understanding of the determinants of the metabolic syndrome during adolescence might provide preventive interventions for improving health outcomes in adulthood.

Enzyme replacement therapy improves joint motion and outcome of the 12-min walk test in a mucopolysaccharidosis type VI patient previously treated with bone marrow transplantation.

Mucopolysaccharidosis type VI (MPS VI; Maroteaux–Lamy syndrome, OMIM #253200) is a rare disorder involving multiple organs and manifested particularly by severe skeletal abnormalities. Bone marrow transplantation (BMT) improves cardiopulmonary function and facial features, but has limited success in ameliorating skeletal abnormalities and short stature. Here, we report the outcome of enzyme replacement therapy (ERT) with recombinant human arylsulfatase‐B (ASB, Naglazyme®, BioMarin, Novato, CA) in an MPS VI patient who received BMT 10 years prior to ERT induction. Administration of weekly Naglazyme® for 18 months was effective in improving range of motion in several joints [shoulders (improvement of flexion (Right/Left): 40°/55°; improvement of extension 30°/40°; improvement of abduction 10°/10°), elbows (improvement of flexion 25°/25°; improvement of extension 10°/15°), hips (improvement of flexion 25°/10°), and knees (improvement of flexion 45°/40°; improvement of extension 50°/60°)]. Improvement in the outcome of the 12‐min walk test (70% increase) and 3‐min stair‐climbing test (29% increase) was also noted after ERT. Because ERT improved clinical features in an MPS VI patient who had undergone prior BMT, the role of ERT post successful BMT in MPS VI needs further investigation.

A study of the relationship between clinical phenotypes and plasma iduronate-2-sulfatase enzyme activities in Hunter syndrome patients

Purpose Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a rare lysosomal storage disorder caused by iduronate-2-sulfatase (IDS) deficiency. MPS II causes a wide phenotypic spectrum of symptoms ranging from mild to severe. IDS activity, which is measured in leukocyte pellets or fibroblasts, was reported to be related to clinical phenotype by Sukegawa-Hayasaka et al. Measurement of residual plasma IDS activity using a fluorometric assay is simpler than conventional measurements using skin fibroblasts or peripheral blood mononuclear cells. This is the first study to describe the relationship between plasma IDS activity and clinical phenotype of MPS II. Methods We hypothesized that residual plasma IDS activity is related to clinical phenotype. We classified 43 Hunter syndrome patients as having attenuated or severe disease types based on clinical characteristics, especially intellectual and cognitive status. There were 27 patients with the severe type and 16 with the attenuated type. Plasma IDS activity was measured by a fluorometric enzyme assay using 4-methylumbelliferyl-α-iduronate 2-sulphate. Results Plasma IDS activity in patients with the severe type was significantly lower than that in patients with the attenuated type (P=0.006). The optimal cut-off value of plasma IDS activity for distinguishing the severe type from the attenuated type was 0.63 nmol·4 hr-1·mL-1. This value had 88.2% sensitivity, 65.4% specificity, and an area under receiver-operator characteristics (ROC) curve of 0.768 (ROC curve analysis; P=0.003). Conclusion These results show that the mild phenotype may be related to residual lysosomal enzyme activity.

Mutational spectrum in eight Korean patients with 3‐methylcrotonyl‐CoA carboxylase deficiency

To the Editor : Isolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is a rare metabolic disorder inherited as an autosomal recessive trait (1). Clinical presentation is extremely variable, ranging from severe neurological abnormalities and death in infancy to asymptomatic adults detected in family studies or in mothers because of positive findings on screening of their unaffected newborn babies (2, 3). By expansion of tandem mass spectrometry (MS/MS) in neonatal screening, MCC deficiency appears to be the most frequently detected organic aciduria, with an overall frequency of approximately 1 in 50,000 (2). Most infants detected by neonatal screening appear clinically normal and remain healthy (2, 4, 5). However, some children who were diagnosed on neonatal screening tests and lost to follow-up presented with profound ketoacidosis during a later intercurrent illness (6). Herein, we have described the mutational spectrum in eight Korean patients with MCC deficiency (six unrelated families). All the patients were full term with appropriate birth weight and were detected by MS/MS in neonatal screening. Their parents were non-consanguineous. None of the patients showed clinical symptoms, such as seizure, failure to thrive from birth, hypotonia, hypoglycemia, psychomotor retardation, or other neurological symptoms. On physical examination, all of them showed a normal percentage of height and weight, and vital signs were normal. Patient 1 and patient 2, who were elder brothers of patient 3, were diagnosed by family member screening just after diagnosis of patient 3. With parental informed consent, peripheral venous blood samples were collected from each of the subjects. All exons of the MCCC1 and MCCC2 genes were amplified by polymerase chain reaction on a thermal cycler (Applied Biosystems, Foster City, CA) using primer pairs designed by the authors. Numbering of nucleotide positions was done according to the complementary DNA sequences of MCCC1 and MCCC2, and the GenBank accession number was NM_020166.3 and NM_022132.4, respectively. Sequence variation was described according to the recommendations of the Human Genome Variation Society (http://www.hgvs.org/mutnomen). Of the six probands, excluding two siblings (patients 1 and 2) of patient 3, a total of 11 mutant alleles were detected. Eight different mutant alleles were identified (Table 1) and six of them were novel mutations (c.842G>A of MCCC1, c.1375C>T of MCCC2, c.1666A>G of MCCC2, c.1614A>T of MCCC2, c.826T>C of MCCC1, and c. 449_450delTG of MCCC2 ). Missense mutations constitute the absolute majority of mutations in our study. Considering that patients 1–3 were siblings, there might be no mutational hotspot in Korean patients with MCC deficiency. It is worthwhile to note that c.838G>T of MCCC2, which was described in one Japanese patient who presented with Reye-like syndrome at the age of 1 year (7), was the most common mutation type [25% (3 of 12)]. According to a study by Dantas et al. (5), c.1155A>C (p.R385S) of MCCC1 (four alleles of 28 probands, 7.1%) and c.295G>A (p.E99Q) of MCCC2 and c.1574+1G>A (p.F497_V526>GfsX4) of MCCC2 (each of three alleles of 28 probands, 5.4%) were of particular relevance. These mutations were not found in our patients; therefore, a difference exists between races. c.214C>T of MCCC2 in patient 4 has been reported in one Turkish patient with no clinical symptoms, who was detected by a neonatal screening test (5). Both known mutations c.838G>T of MCCC2 and c.214C>T of MCCC2 were not frequent mutations. Taking several studies (5, 7–10) together, exon 11 of MCCC1 and exons 6 and 11 of MCCC2 were of particular relevance. In our study, all the three mutations of MCCC1 are on exon 8,

Diagnosis and constitutional and laboratory features of Korean girls referred for precocious puberty

Purpose Precocious puberty is defined as breast development before the age of 8 years in girls. The present study aimed to reveal the diagnosis of Korean girls referred for precocious puberty and to compare the constitutional and endocrinological features among diagnosis groups. Methods The present study used a retrospective chart review of 988 Korean girls who had visited a pediatric endocrinology clinic from 2006 to 2010 for the evaluation of precocious puberty. Study groups comprised fast puberty, true precocious puberty (PP), pseudo PP, premature thelarche, and control. We determined the height standard deviation score (HSDS), weight standard deviation score (WSDS), and body mass index standard deviation score (BMISDS) of each group using the published 2007 Korean growth charts. Hormone tests were performed at our outpatient clinic. Results The PP groups comprised fast puberty (67%), premature thelarche (17%), true PP (15%), and pseudo PP (1%). Advanced bone age and levels of estradiol, basal luteinizing hormone (LH), and peak LH after gonadotropin-releasing hormone stimulation testing were significantly high in the fast puberty and true PP groups compared with the control group. HSDS, WSDS, and BMISDS were significantly higher in the true PP group than in the control group (P<0.05). Conclusion The frequent causes of PP were found to be fast puberty, true PP, and premature thelarche. Furthermore, BMISDS were significantly elevated in the true PP group. Therefore, we emphasize the need for regular follow-up of girls who are heavier or taller than others in the same age group.