Bilateral stenosis of carotid siphon in Hutchinson-Gilford progeria syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disease, caused by a de novo mutation of lamin-A gene, LMNA G608G. Accumulation of abnormal lamin-A (progerin) compromises nuclear membrane integrity and results in the accelerated senescence. Affected patients show a typical feature of birdlike face, alopecia, sclerotic skin, loss of subcutaneous fat, and short stature with advancing years. Neonatal scleroderma is the first presentation, although early diagnosis is challenging. The leading cause of death is cardio-/cerebro-vascular accidents associated with atherosclerosis. However, not all findings may recapitulate the aging process. We herein report a 9-year-old Japanese male with HGPS who developed cerebral infarction. The genetic study of peripheral blood-derived DNA determined a heterozygous c.1824C>T mutation, p.G608G. Telomere length of lymphocytes was normal. Bilateral stenosis of carotid siphons was prominent, while systemic arteriosclerosis was unremarkable assessed by the ankle-brachial index, carotid ultrasound imaging and funduscopic study. HGPS patients have marked loss and functional defects in vascular smooth muscle cells, leading to the vulnerability to circulatory stress. Symmetrical stenosis of siphons might occur as a distinctive cerebral vasculopathy of HGPS, rather than simple vascular senescence. Peripheral blood study on LMNA G608G and telomere length could screen progerias in infancy for early therapeutic intervention.

A novel mutation of human liver alanine:glyoxylate aminotransferase causes primary hyperoxaluria type 1: immunohistochemical quantification and subcellular distribution.

A novel alanine:glyoxylate aminotransferase (AGT) mutation involved in primary hyperoxaluria type 1 (PH1) was studied in Japanese patients. Two mutations in exon 7, c.751T>A and c.752G>A, lead to a W251K amino acid substitution. Proband 1 (patient 1) was homozygous for the W251K mutation allele (DDBJ Accession No. AB292648), and AGT-specific activity in the patient's liver was very low. To reveal the cause of the low enzymatic activity, the intracellular localization of AGT (W251K) was studied using immunohistochemistry and immunoelectron microscopy. The latter analysis showed that patient 2 had only one-fifth of the normal AGT expression per catalase, suggesting impairment of AGT (W251K) dependent transport into peroxisomes. Peroxisomal transport of human AGT is believed to be dependent on the presence of the type 1 peroxisomal targeting sequence. The C-terminal tripeptide of AGT, KKL is necessary for peroxisomal targeting. In cultured cells, EGFP-AGT (W251K) localized both in the peroxisome and cytosol. These results were consistent with the data obtained from liver analysis of patient 2. The subcellular distribution of AGT (W251K) and the results from a random mutagenesis study suggest that KKL is necessary for peroxisomal targeting of human AGT, but additional signal other than KKL may be necessary.

Survival and late effects on development of patients with infantile brain tumor.

BACKGROUND: Most infants with brain tumor may have a poor prognosis. The aim of the present study was to retrospectively analyze the survival and outcome with regard to mental and physical development in 11 subjects with brain tumor; these tumors were diagnosed when the patients were under 1 year of age. METHODS: The histological diagnoses of these tumors were astrocytoma, n = 3; pineocytoma, n = 2; teratoma, n = 1; ependymoma, n = 1; atypical teratoid/rhabdoid tumor, n = 1; glioblastoma, n = 1; medulloblastoma, n = 1; and choroid plexus papilloma, n = 1. Surgical resection was performed in eight patients, and adjuvant chemotherapy was administered to all except one patient with choroid plexus papilloma. Radiotherapy was additionally performed for four of the 10 chemotherapy patients. RESULTS: Six patients survived. Among the surviving patients, five were under no treatment for 50-167 months after the diagnosis (median duration, 89 months), while one received chemotherapy for 20 months. Five patients exhibited mental retardation, and one patient experienced normal development after surgical removal of his choroid plexus papilloma. Diencephalic syndrome developed in one patient with pilomyxoid astrocytoma that necessitated hormone replacement therapy, and bodyweight over +2 SD was observed in two patients. The remaining five patients died 11-111 months after diagnosis (median duration, 24 months). CONCLUSION: The prognosis of infantile brain tumor with regard to mortality and developmental outcome remains poor. Furthermore, survivors require comprehensive medical and social support for an extended period.