Satoshi Sumi

Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency.

Abstract. Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency is a common inherited condition characterized by the abnormal accumulation of inosine triphosphate (ITP) in erythrocytes. The genetic basis and pathological consequences of ITPase deficiency are unknown. We have characterized the genomic structure of the ITPA gene, showing that it has eight exons. Five single nucleotide polymorphisms were identified, three silent (138G→A, 561G→A, 708G→A) and two associated with ITPase deficiency (94C→A, IVS2+21A→C). Homozygotes for the 94C→A missense mutation (Pro32 to Thr) had zero erythrocyte ITPase activity, whereas 94C→A heterozygotes averaged 22.5% of the control mean, a level of activity consistent with impaired subunit association of a dimeric enzyme. ITPase activity of IVS2+21A→C homozygotes averaged 60% of the control mean. In order to explore further the relationship between mutations and enzyme activity, we examined the association between genotype and ITPase activity in 100 healthy controls. Ten subjects were heterozygous for 94C→A (allele frequency: 0.06), 24 were heterozygotes for IVS2+21A→C (allele frequency: 0.13) and two were compound heterozygous for these mutations. The activities of IVS2+21A→C heterozygotes and 94C→A/IVS2+21A→C compound heterozygotes were 60% and 10%, respectively, of the normal control mean, suggesting that the intron mutation affects enzyme activity. In all cases when ITPase activity was below the normal range, one or both mutations were found. The ITPA genotype did not correspond to any identifiable red cell phenotype. A possible relationship between ITPase deficiency and increased drug toxicity of purine analogue drugs is proposed.

Genetic influences on the broad spectrum of autism: study of proband-ascertained twins.

An investigation of genetic structures underlying autistic traits was performed with samples from twins for which at least one proband had been ascertained as having autism spectrum disorders (ASDs) in our catchment area. In order to adjust for recent concepts of autism, we employed criteria for the broad spectrum of disease and the childhood autism rating scale (CARS) for quantitative assessment. The CARS test was performed on 45 twin pairs (19 monozygotic, 26 dizygotic) detected with a regional routine screening system. The obtained CARS scores were subjected to structural equation modeling (SEM), incorporating sex differences for each causal influence ascertainment correction, using the Mx software. A best fitting model of causal influences on autistic traits measured continuously, incorporating additive genetic (A) and non‐shared environmental influences (E), was generated. With this AE model, the estimated heritability was 0.73 for males and 0.87 for females, based on the continuous CARS scores. There was no evidence for the existence of sex‐specific genetic influences. Autistic traits were highly heritable in twins with even broad spectrum of autism, corresponding to the results of early studies based on classical autism. Additive genetic factors were more influential in females than males.

Sibling risk of pervasive developmental disorder estimated by means of an epidemiologic survey in Nagoya, Japan

AbstractBroad-spectrum autism, referred to as pervasive developmental disorder (PDD), may be associated with genetic factors. We examined 241 siblings in 269 Japanese families with affected children. The sibling incidence of PDD was 10.0% whereas the prevalence of PDD in the general population in the same geographic region was 2.1%. Both of these rates are higher than those reported previously, probably because of the expanded clinical criteria applied. The prevalence in males of the general population was 3.3% and that in females was 0.82%. The sibling incidences were 7.7 and 20.0% for families in which the probands were male and female, respectively. Because the reversed sex ratios correspond to the general rule for a multifactorial threshold model, we suggest that most PDD cases result from the cumulative effects of multiple factors (mostly genetic). The sibling incidences were 0 and 10.9% for families in which the proband had low and normal birth-weight, respectively, suggesting the risk is lower in families with low-birth-weight probands.

Population and family studies of dihydropyrimidinuria: Prevalence, inheritance mode, and risk of fluorouracil toxicity

To evaluate the prevalence of dihydropyrimidinuria (DHPuria), we analyzed urine samples from 21,200 healthy Japanese infants, and found two cases of DHPuria without clinical symptoms. Based on this result, we estimated the prevalence to be approximately 1/10,000 births in Japan. In addition, we analyzed pyrimidine catabolism on a previously reported family with an adult DHPuria case. We newly identified the sister of the propositus as the second case of DHPuria in this family, because she excreted large amounts of dihydrouracil and dihydrothymine. The parents and the child of the propositus showed slight increases of dihydrouracil and dihydrothymine. This is the first family with 2 cases of DHPuria, indicating that DHPuria is an inherited condition. To determine the inheritance of DHPuria in this family and to examine the risk of 5-fluorouracil (5-FU) toxicity, a uracil loading test was performed on the parents. Urinary dihydrouracil concentrations in the parents after the loading were several times higher than those in normal control persons, the finding being consistent with DHPuria heterozygotes. This, along with data on the propositus, his sister, and his child, indicates that DHPuria is an autosomal recessive condition. In addition, DHPuria homozygotes may have a high risk of 5-FU toxicity, while the risk is relatively low in heterozygotes.

Dihydropyrimidinase deficiency : structural organization, chromosomal localization, and mutation analysis of the human dihydropyrimidinase gene

Dihydropyrimidinase (DHP) deficiency (MIM 222748) is characterized by dihydropyrimidinuria and is associated with a variable clinical phenotype. This disease might be associated with a risk of 5-fluorouracil toxicity, although no cases have been reported. We present here both the molecular characterization of the human DHP gene and, for the first time, the mutations causing DHP deficiency. The human DHP gene spans >80 kb and consists of 10 exons. It has been assigned to 8q22, by FISH. We performed mutation analysis of genomic DNA in one symptomatic and five asymptomatic individuals presenting with dihydropyrimidinuria. We identified one frameshift mutation and five missense mutations. Two related Japanese adult subjects were homozygous for the Q334R substitution, whereas two other, unrelated Japanese infant subjects were heterozygous for the same mutation, but this mutation is not common in the Japanese population. A Caucasian pediatric patient exhibiting epileptic attacks, dysmorphic features, and severe developmental delay was homozygous for W360R. Using a eukaryotic expression system, we showed that all mutations reduced enzyme activity significantly, indicating that these are crucial DHP deficiency-causing mutations. There was no significant difference, in residual activity, between mutations observed in the symptomatic and those observed in the asymptomatic individuals.

Automated screening system for purine and pyrimidine metabolism disorders using high-performance liquid chromatography

An automated screening system for purine and pyrimidine metabolism disorders using high-performance liquid chromatography (HPLC) with column switching is described. The system consists of a reversed-phase column, a cation-exchange column, a column switch, four sets of ultraviolet absorbance detectors, a microcomputer and other conventional equipment. As this system permits the simultaneous determination of urinary orotic acid, uracil, dihydrouracil, pseudouridine, xanthine, 2,8-dihydroxyadenine and succinyladenosine, it offers a useful method for the detection of orotic aciduria, dihydropyrimidine dehydrogenase deficiency, dihydropyrimidinuria, xanthinuria, adenine phosphoribosyltransferase deficiency and adenylosuccinase deficiency.

Comprehensive Comparison of Self-administered Questionnaires for Measuring Quantitative Autistic Traits in Adults

We comprehensively compared all available questionnaires for measuring quantitative autistic traits (QATs) in terms of reliability and construct validity in 3,147 non-clinical and 60 clinical subjects with normal intelligence. We examined four full-length forms, the Subthreshold Autism Trait Questionnaire (SATQ), the Broader Autism Phenotype Questionnaire, the Social Responsiveness Scale2-Adult Self report (SRS2-AS), and the Autism-Spectrum Quotient (AQ). The SRS2-AS and the AQ each had several short forms that we also examined, bringing the total to 11 forms. Though all QAT questionnaires showed acceptable levels of test–retest reliability, the AQ and SRS2-AS, including their short forms, exhibited poor internal consistency and discriminant validity, respectively. The SATQ excelled in terms of classical test theory and due to its short length.

Dihydropyrimidinuria: the first case in Japan.

Dihydropyrimidinuria (McKusick 222748) is a recently described disorder of pyrimidine metabolism that presents neurological symptoms different in degree. Only two cases have been reported to date (Duran et al, 1991; Henderson et al, 1993). The patients with dihydropyrimidinuria excrete large amount of dihydrouracil and dihydrothymine, and moderate amount of uracil and thymine in urine. Therefore this disease is thought to be caused by a deficiency of dihydropyrimidine amidohydrolase (DHPase; EC 3.5.2.2), the second step of pyrimidine base catabolism. The first case, reported by Duran et al (1991), was hospitalized for convulsion and disturbed consciousness at the age of 8 weeks, but whose subsequent development had been normal. The second case reported by Henderson et al (1993) presented severe developmental delay. These two patients were discovered by the urinary gas chromatography mass spectrometry (GC-MS) analysis for the neurological sick children. We report here another case of dihydropyrimidinuria which is the first case in Japan and probably the third worldwide. We discovered her by using high-performance liquid chromatography (HPLC) at the mass screening program.

Genetic correlation between autistic traits and IQ in a population-based sample of twins with autism spectrum disorders (ASDs)

Although there is accumulating evidence that intelligence quotient (IQ) indexes some aspects of the autistic spectrum disorders (ASDs), the causal relationship between autistic traits and IQ remains controversial. We examined the sources of covariation between autistic traits and IQ. As males have a four times greater risk of ASDs than females, gender-specific effects were also explored. Autistic traits and IQ were assessed in 45 twin male–male, female–female and opposite-sex pairs ascertained by the regional screening system in Nagoya, Japan. Sex-limited Cholesky structural equation models were used to decompose the correlations between autistic traits and IQ into genetic and environmental components, including sex-specific factors. Genetic correlations between autistic traits and IQ were high and not significantly different between boys and girls (−0.94 and −0.95, respectively), but genetic factors underlying the autistic traits were not entirely shared with the IQ. The individual-specific environmental correlation between autistic traits and IQ was estimated at −0.29 for boys and −0.59 for girls. There is a substantial overlap between the genetic factors that influence individual variation in autistic traits and IQ, irrespective of gender. The individual life experiences that increase autistic traits, however, have a moderate overlap with those that contribute to individual IQs.

Allele frequency of inosine triphosphate pyrophosphatase gene polymorphisms in a Japanese population.

The enzyme inosine triphosphate pyrophosphatase (ITPase) catalyses the pyrophosphohydrolysis of ITP to IMP. ITPase deficiency is a clinically benign autosomal recessive condition characterised by the abnormal accumulation of ITP in erythrocytes. A deficiency of ITPase may predict adverse reactions to therapy with the thiopurine drug 6‐mercaptopurine and its prodrug azathioprine. In this study, we examine the frequencies of ITPA polymorphisms in 100 healthy Japanese individuals. The allele frequency of the 94C > A variant in the Japanese sample was 0.135 (Caucasian allele frequency 0.06). The IV2 + 21A > C polymorphism was not found in Japanese (Caucasian allele frequency 0.130). Allele frequencies of the 138G > A, 561G > A and 708G > A polymorphisms were 0.57, 0.18 and 0.06 respectively in the Japanese population, and with the exception of the 138G > A polymorphism, similar to allele frequencies in Caucasians.