A cluster of lysinuric protein intolerance (LPI) patients in a northern part of Iwate, Japan due to a founder effect. The Mass Screening Group.

Lysinuric protein intolerance is an autosomal recessive disease characterized by defective transport of the dibasic aminoacids. Mutational analysis of LPI patients in the northern part of Japan revealed that six were homozygous for the R410X mutation and two others were compound heterozygotes of R410X and other unknown mutations. In the population epidemiology study in a local cluster in the northern part of Iwate, ten heterozygotes were found in 1190 newborn babies leading to an estimated LPI incidence of 1/57,000. Polymorphism analysis revealed two major alleles, A and B, in intron 8. While the population frequency of allele A was 0.9 and that of allele B was 0.1 in the northern part of Japan the R410X mutations were exclusively on allele B in 31 chromosomes suggesting a founder effect. Genetic analysis in patients revealed strong linkage disequilibrium with D14S283 and TCRA indicating that the R410X mutation occurred before at least 130 generations ago (about 2600 years). The R410X mutation was shown to be useful as a molecular marker for screening LPI patients in the northern part of Japan.

SLC7A7 genomic structure and novel variants in three Japanese lysinuric protein intolerance families.

Lysinuric protein intolerance (LPI) is a rare inherited disease caused by defective transport of the dibasic amino acids at the basolateral membranes of epithelial cells in the renal tubules and small intestine. The metabolic defect leads to brain dysfunction caused by hyperammonemia with a functional impairment of the urea cycle. Recently, mutations in the human SLC7A7 cDNA coding for y(+)LAT-1, which express dibasic amino acid transport activity, were reported to be responsible for LPI. In the present study, we examined the genomic structure of SLC7A7 by DNA sequencing of PCR products, and determined that the gene had 11 exons and 10 introns spanning about 18 kb of genomic DNA. We also identified an alternative RNA splicing at the 5' untranslated region of the SLC7A7 mRNA in human peripheral blood leukocytes, cultured lymphoblasts, and fibroblasts. As a result of mutational analysis of SLC7A7 in three Japanese LPI families, we found a nonsense mutation (R410X), a splicing mutation(911+1G>A) in intron 4, and four silent polymorphisms (201C/T, 445A/G, 784C/T, 946T/C). Identification of the genomic structure of SLC7A7 may provide a molecular basis for a genetic survey for LPI.

Axial spondylometaphyseal dysplasia.

UNLABELLED: We present a previously undescribed skeletal dysplasia characterized by mild platyspondyly, small thorax with cupping of the anterior ends of the ribs, irregular proximal femoral metaphyses, and lacy appearance of the iliac wings. Two of the three cases were siblings. Retinitis pigmentosa and optic atrophy are associated findings. CONCLUSION: We describe a new type of spondylometaphyseal dysplasia (SMD) and propose the name axial SMD.

Patent ductus venosus with hypoplastic right hepatoportal system in a young child born with asymmetric intra-uterine growth retardation.

We report a functioning ductus venosus with hypoplasia of the right hepatoportal system in a 2-year-old child born with asymmetric intra-uterine growth retardation. Postprandial galactosaemia and hyperammonaemia were clues to diagnosis of portal-systemic shunt through the patent ductus venosus, which was confirmed by ultrasonography and angiography.

Lissencephaly with congenital muscular dystrophy and ocular abnormalities: cerebro-oculo-muscular syndrome.

A Japanese male infant with lissencephaly, congenital muscular dystrophy (CMD), and ocular abnormalities is described. This patient represents features of the cerebro-oculo-muscular syndrome. Cranial computerized tomography revealed diffuse agyria, low density of the white matter, and hypoplasia of the cerebellar vermis. Brain histology suggested type II lissencephaly. These findings are correlated with other similar conditions, such as Walker-Warburg syndrome, Fukuyama-type CMD, and muscle, eye and brain disease.

Prenatal diagnosis of Hurler's syndrome--biochemical studies on the affected fetus.

A prenatal diagnosis of Hurler's syndrome was made in a pregnancy at risk in a family with two affected children. The fetus was diagnosed as having Hurler's syndrome on the basis of a deficiency of alpha-L-iduronidase in the cultured amniotic cells. The glycosaminoglycans (GAG) content in the supernatant of the amniotic fluid was increased about 1.5 fold compared with that in the control, and increases of heparan sulfate and dermatan sulfate were observed on electrophoresis. The diagnosis could be confirmed by the deficiencies of alpha-L-iduronidase in the liver and brain from the affected fetus. GAG content in the liver from the affected fetus was increased approximately 10 fold as compared with that in the control fetal liver, and most of the GAG were degraded. The GAG content was observed to be increased two fold in the brain, and dermatan sulfate, which was not detected in normal fetal brain, was identified. beta-Galactosidase activities in the affected liver and brain were decreased to 30-50% of the control, and an altered hexosaminidase A was also observed in the liver.