Tomomi Kato

Mutational and structural analysis of Japanese patients with mucopolysaccharidosis type II

AbstractWe investigated mutations of the iduronate-2-sulfatase (I2S) gene and structural characteristics of I2S to clarify genotype/phenotype relationships in 18 Japanese patients with mucopolysaccharidosis type II. The I2S gene was analyzed in five patients with a severe phenotype and in 13 patients with an attenuated phenotype. The tertiary structural model of the human I2S was constructed by homology modeling using the arylsulfatase structure as a template. We identified four missense mutations and a nonsense mutation in the severe phenotype; four missense, two nonsense, three frame shifts, and one each of splice and amino acid deletion in the attenuated phenotype. Seven of them (L73del, Q75X, G140R, C171R, V401 fs, C422 fs, and H441 fs) were novel mutations. Structural analysis indicated that the residues of the mutations found in the severe phenotype would have direct interactions with the active site residues or should break the hydrophobic core domain of I2S, whereas residues of the missense mutations found in the attenuated phenotype were located in the peripheral region. In addition, effects by deletion or frameshift mutations could also be interpreted by the structure. Structural analysis of mutant proteins would help in understanding the genotype/phenotype relationships of Hunter disease.

Evaluation of ADL in patients with Hunter disease using FIM score

MPS type II (Hunter disease) results from deficiency of the lysosomal enzyme iduronate-2-sulfate sulfatase. Two forms of the disease have been recognized, based on absence or presence of progressive intellectual deterioration. This study aimed to assess activities of daily life (ADL) in 27 Hunter disease-affected Japanese patients, using a modified version of the functional independence measure (FIM). Scores of ADL for patients with a severe phenotype were significantly lower than those of control children. Total scores were highest around 5-7 years old, then progressively decreased, and scores <40 were obtained with patients aged 9 years or more. In contrast to motor scores, cognitive scores decreased rapidly, generally reaching a minimum score at around 7 years old. On the other hand, in children with attenuated phenotype, total scores increased progressively with age similar to control children. Two children who had the highest grades at elementary school showed maximum scores. However, all adult patients did not show maximum total scores, and 3 of 4 patients over 25 years old showed decreasing scores. Two children and two adults showed significant lower scores compared with other patients, suggesting an intermediate form from the view of ADL. This study elucidated the precise clinical state of Hunter disease with distinct numerical scores, in addition to previously described narrative data. To maintain the QOL of the patients better, they and their family need to know what specific difficulties they encounter, in which period they encounter them, and what support can fix them. Further ADL investigations with larger populations and/or long-term sequential examination could help the patients and family to understand them well.

Psychological status of patients with mucopolysaccharidosis type II and their parents

Background:  The aim of the present study was to delineate the psychological status of 10 patients with the attenuated phenotype of mucopolysaccharidosis type II (MPS‐II) and their parents (six fathers and five mothers) for the improvement of clinical management.

Neurodevelopmental outcomes of infants with birth weights of less than 1000 g: comparison between periods before and after the introduction of surfactant

In order to assess the effect of surfactant therapy on the neurodevelopmental outcome of infants with a birth weight of less than 1000 g, we evaluated the outcome of 169 infants in the period after introduction of the surfactant (January 1989 to May 1993) by a follow-up of 6 years on the average, and compared these results to those of 107 infants in our previous study before the surfactant period (October 1981 to March 1986) by a follow-up of 7.5 years on the average. Nursery survival rate was significantly increased from 69.3% in the presurfactant period to 80% in the surfactant period (P < 0.05). However, there were no substantial differences in the neurodevelopmental outcomes between the two periods. This enhanced survival rate without the improvement of outcome resulted in a proportionate increase in normal and impaired survivors.

Thyroid cancer in a case with the Alagille syndrome

A 19‐year‐old woman with the Alagille syndrome developed papillary thyroid carcinoma with lung metastasis. She was diagnosed as having Alagille syndrome at the age of 8. Following total thyroidectomy and lymph nodes dissection, iodine‐131 therapy was conducted for local and distant metastases. This is the first report of a case of thyroid cancer accompanying Alagille syndrome.

Interstitial deletion of the short arm of chromosome 10: Report of a case and review of the literature

SummaryThe fifth patient with an interstitial deletion of the short arm of chromosome 10 is described. She showed most of the features observed in other known patients at age 20, including psychomotor retardation, distinct facial dysmorphism, abnormally shaped skull and cardiac malformation, while she did not show any growth retardation. The elevation of serum IgG level was observed from age 15, but she did not show DiGeorge syndrome. These differences would be explained by the differences in the amount of deleted segments using high resulution chromosome banding and molecular methods.

Developmental changes of radiological findings in Fukuyama-type congenital muscular dystrophy

Fukuyama-type congenital muscular dystrophy (FCMD) is characterized by congenital muscular dystrophy and associated with neuropathological anomalies. However, the issue of whether the radiological findings of white-matter lesions represent delayed myelination, demyelination or other problems remains controversial. We present serial radiological findings, including MR spectroscopy (MRS), in a child with FCMD. These findings indicate a correlation between the imaging abnormalities and the choline/creatine ratio, suggesting the possible usefulness of MRS in addition to MRI for following FCMD patients.

Retinitis pigmentosa and mucopolysaccharidosis type II: an extremely attenuated phenotype

A 29-year-old Japanese man had had decreased visual acuity (6/15) and visual field in the dark for 10 years. He had been healthy and intelligent. His height (168 cm), head circumference (57 cm), and general appearance of the face and posture were normal (Fig. 1a). Very mild contracture of the fingers and elbows was noted (Fig. 1b), which suggested the possibility of mucopolysaccharidosis. Other joints, skin, hair, teeth, and tongue were normal. Liver and spleen were not palpable. Funduscopic examination revealed diffuse retinal atrophy and bone spicule-like pigmentation (Fig. 1c). Visual disturbance was slowly progressive, and the present visual field is reduced by 80 degrees. Mild aortic valve regurgitation and moderate hearing difficulty were detected. Bone radiography showed no finding of dysostosis multiplex. Urinary glycosaminoglycan (GAG) was increased (48.9 mg/g creatinine, control <10), and heparan sulfate and dermatan sulfate were the major components. Iduronate-2-sulfatase (I2S) activity in white blood cells was decreased (0.2 nmol/h per mg protein, control 15–28); however, arylsulfatase A activity was within the normal range. A missense mutation C171R (511T>C) was identified in the I2S gene. Thus the patient was diagnosed as having mucopolysaccharidosis type II (MPS II, Hunter syndrome). Patients with the attenuated phenotype of MPS II usually manifest systemic findings from childhood (Young and Harper 1982), and retinitis pigmentosa is one of these systemic findings (Ashworth et al 2006). Our report implies the presence of undiagnosed adult patients with MPS II who have retinitis pigmentosa as the sole manifestation. Heart valve disorder or hearing impairment may also be a cardinal sign in adult MPS II patients.

Portal hypertension in a patient with Hunter disease

SummaryHepatosplenomegaly is one of the cardinal signs of Hunter disease; however, portal hypertension has not been described. We report portal hypertension in an adult Hunter patient with the attenuated phenotype.