Mitsukazu Mamada

Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications

Abstract. Propionic acidemia [MIM 606054] is a form of organic acidemia caused by genetic deficiency of propionyl-CoA carboxylase (PCC) and characterized by attacks of severe metabolic acidemia and hyperammonemia beginning in the neonatal period or in early infancy. There are, however, patients who have higher PCC activities and present later with unusual symptoms, such as mild mental retardation or extrapyramidal symptoms, sometimes even without metabolic acidosis. Through the neonatal screening of more than 130,000 Japanese newborns we detected a frequency of patients with propionic acidemia more than ten times higher than previously reported, most of them with milder phenotypes. The mutational spectrum was quite different from that of patients with the severe form and there was a common mutation (Y435C) in the β subunit of the PCC gene (PCCB). Since patients with the mild form could present with unusual symptoms and therefore could easily remain unrecognized, it is important to identify those patients and clarify their natural history. Molecularly, one of the mutations (A1288C) caused an unusual pattern of multiple exon skipping and another unidentified mutation lead to the absence of mRNA. Taking into consideration previous findings regarding PCCB mutations, it appears that this gene is particularly prone to posttranscriptional modifications such as missense mediated exon skipping, mRNA decay, or rapid product degradation.

Living-donor liver transplantation for propionic acidaemia.

Summary: Three patients with the severe form of propionic acidaemia were treated with living-donor liver transplantation (LDLT). The procedure was successful for all patients and the incidence of metabolic decompensation was reduced dramatically even without protein restriction. Biochemically, however, the improvement was not significant and the patients continued to excrete large amounts of propionic acid metabolites. One of the patients experienced a severe acidaemic episode 3 years after transplantation. LDLT has a beneficial effect on the care of severely affected patients since it reduces the risk of metabolic decompensation and improves the quality of life with less strict dietary control. Adequate protein restriction and medication need to be maintained even after successful transplantation.

Analysis of the SRY gene in Turner syndrome patients with Y chromosomal material

Editor—Turner syndrome is one of the most common chromosomal abnormality syndromes affecting 1 in 2500 liveborn females. The syndrome is characterised by short stature, gonadal dysgenesis, congenital heart disease, renal anomalies, and a variety of somatic features including neck webbing, cubitus valgus, short neck, and widely set nipples. Nearly half of the patients have a classical 45,X karyotype while others have structurally abnormal sex chromosomes (for example, 46,X,i(Xq)) or are mosaics with other cell lines with normal (46,XX) or abnormal sex chromosomes.1-4 Among these, patients with Y chromosomal material require specific attention since many of these 45,X/46,XY Turner syndrome patients develop gonadoblastoma or dysgerminoma later in life.5 6 Conventional chromosomal analysis indicates that 4-20% of patients with Turner syndrome have a Y chromosome or its derivatives.1-4 These figures could be even higher, since the more sensitive PCR based analysis has shown that 15-60% of cytogenetically 45,X females have Y chromosomal material.7-9 These findings mean that 10-50% of all Turner syndrome patients have Y chromosomal material and therefore are, to some extent, at risk of developing gonadoblastoma. A more precise understanding of the mechanism leading to generation of a 45,X/46,XY karyotype is therefore important for providing better care for these patients. Karyotypes such as 45,X/46,XY are presumably caused by mitotic loss of the Y chromosome from the originally 46,XY fetus. It is not known, …

Prevalence of Mutations in the FGFR3 Gene in Individuals with Idiopathic Short Stature.

FGFR3 (fibroblast growth factor receptor 3) is a gene responsible for the most common form of osteodysplasia, achondroplasia, which results in extreme short stature. An allelic disorder, hypochondroplasia, however, presents with a much milder phenotype and is sometimes indistinguishable from idiopathic short stature. In this study, in order to test the possibility of the mildest end of hypochondroplasia being labeled as idiopathic short stature and the possibility of polymorphism of FGFR3 acting as one of the stature genes of normal individuals, we examined the prevalence of sequence alterations of the FGFR3 gene among individuals diagnosed clinically with idiopathic short stature. Sequencing analysis of all exons of the FGFR3 gene on 54 individuals with idiopathic short stature did not reveal any sequence variations related to the stature of the individuals. These results suggest that hidden hypochondroplasia among idiopathic short stature individuals is not a common occurrence and the contribution of polymorphism of the FGFR3 gene as a determinant of stature in normal individuals is small if any.

Earlier initiation of GH therapy does not influence adult height but enables earlier start of pubertal induction in children with multiple pituitary hormone deficiency

objective  For patients with GH and gonadotrophin deficiency, adult height and sexual maturation are important not only for their physical but also psychological status. GH therapy is usually initiated soon after diagnosis but the differences in the age for initiation of therapy have not been previously examined. In this study, we assessed the influence of timing of initiation of GH therapy on adult height and the time of initiation of pubertal induction.

Erratum: Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: Presence of a common mutation and possible clinical implications (Human Genetics (2002) 111 (161-165))

In Table 1 and Fig.1, T1304C and T1316C should be A1304G and A1316G, respectively. Since these two mutations were first identified in the antisense orientation, they were erroneously reported as nucleotide changes in the antisense strand. The resultant amino acid changes and the positions of the mutations are correct, and other mutations are correct as well. The authors regret the errors. Tohru Yorifuji · Masahiko Kawai · Junko Muroi · Mitsukazu Mamada · Keiji Kurokawa · Yosuke Shigematsu · Satoko Hirano · Nobuo Sakura · Ichiro Yoshida · Tomiko Kuhara · Fumio Endo · Hiroshi Mitsubuchi · Tatsutoshi Nakahata