Kenji Ihara

Pulmonary Hypertension in Patients With Congenital Portosystemic Venous Shunt: A Previously Unrecognized Association

BACKGROUND. Pulmonary arterial hypertension has been reported to be observed in association with acquired portal hypertension. However, the contribution of congenital anomalies occurring in the portal system to the development of pulmonary arterial hypertension remains to be elucidated. METHODS. Nine patients with congenital portosystemic venous shunt were studied from January 1990 through September 2005. RESULTS. Patent ductus venosus was detected in 5 patients, including 3 patients with an absence of the portal vein. The presence of either a gastrorenal or splenorenal shunt was evident in another 4 patients. Six patients had a history of hypergalactosemia with normal enzyme activities, as seen during neonatal screening. Six (66.7%) of the 9 patients were identified to have clinically significant pulmonary arterial hypertension (mean pulmonary artery pressure: 34–79 mm Hg; pulmonary vascular resistances: 5.12–38.07 U). The median age at the onset of pulmonary arterial hypertension was 12 years and 3 months. Histologic studies of lung specimens, which were available in 4 of the 9 patients with congenital portosystemic venous shunt, showed small arterial microthrombotic lesions in 3 patients. This characteristic finding was recognized even in the congenital portosystemic venous shunt patients without PAH. CONCLUSIONS. This study demonstrated thromboembolic pulmonary arterial hypertension to be a crucial complication in congenital portosystemic venous shunt, and this pathologic state may be latently present in patients with pulmonary arterial hypertension of unknown etiology.

Phenotypic and genetic analyses of T-cell-mediated immunoregulation in patients with Type 1 diabetes.

Aims  To investigate the contribution of regulatory T cells and co‐stimulatory molecules in CD4+ T cells to the development of Type 1 diabetes (T1D).

Genetic Analysis of MMP Gene Polymorphisms in Patients With Kawasaki Disease

Kawasaki disease (KD) is an acute febrile disorder characterized by systemic vasculitis primarily occurring in coronary arteries. Matrix metalloproteinases (MMPs) have been considered to play pathophysiologic roles in the development of coronary artery lesions (CALs); therefore, an evaluation of the genetic contributions of the MMP genes to the development of CALs in KD patients would be beneficial for the prediction of CAL formation. We focused on the known functional single nucleotide polymorphisms (SNPs) in the MMP genes (MMP-2-735C>T, MMP-3-1612 5A/6A, MMP-9-1562C>T, MMP-12-82A>G, and MMP-13-77A>G) and performed the association study between these SNPs and CAL formation in KD. The study population consisted of 44 KD patients with CALs and 92 without CALs and 175 healthy controls. As a result, allele and genotype frequencies of MMP-13-77A>G showed significant differences between KD patients with CALs and without CALs (p = 0.00989 and p = 0.00551, respectively). The estimated frequencies of the G-C haplotype in the MMP-13 gene promoter were significantly lower in KD patients with CALs than in those without CALs. There was no association between other MMP genes and CAL formation. In conclusion, the genetic evaluation by association study demonstrated that the MMP-13 gene, at least in part, contributed to the development of CALs in KD.

Successful bone marrow transplantation in a patient with c‐mpl‐mutated congenital amegakaryocytic thrombocytopenia from a carrier donor

Abstract:  Congenital amegakaryocytic thrombocytopenia (CAMT) is characterized by severe thrombocytopenia and the absence of megakaryocytes in bone marrow. Furthermore, mutation of the c‐mpl gene has been identified as a cause of this disorder. The only curative treatment is allogeneic stem cell transplantation (SCT). The current report describes a patient exhibiting c‐mpl mutation in both alleles who underwent transplantation of allogeneic bone marrow donated by her brother, a c‐mpl mutated carrier, employing a fludarabine‐based conditioning regimen. Engraftment and reconstitution of hematopoietic cells was rapid and without complications. These findings suggest that the carrier donor displaying the c‐mpl mutation can serve as a donor source for SCT.

Novel mutations in five Japanese patients with 3-methylcrotonyl-CoA carboxylase deficiency

AbstractIsolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency appears to be the most frequent organic aciduria detected in tandem mass spectrometry (MS/MS) screening programs in the United States, Australia, and Europe. A pilot study of newborn screening using MS/MS has recently been commenced in Japan. Our group detected two asymptomatic MCC deficiency patients by the pilot screening and collected data on another three MCC deficiency patients to study the molecular bases of the MCC deficiency in Japan. Molecular analyses revealed novel mutations in one of the causative genes, MCCA or MCCB, in all five of the patients: nonsense and frameshift mutations in MCCA (c.1750C > T/c.901_902delAA) in patient 1, nonsense and frameshift mutations in MCCB (c.1054_1055delGG/c.592C > T) in patient 2, frameshift and missense mutations in MCCB (c.1625_1626insGG/c.653_654CA > TT) in patient 3, a homozygous missense mutation in MCCA (c.1380T > G/ 1380T > G) in patient 4, and compound heterozygous missense mutations in MCCB (c.569A > G/ c.838G > T) in patient 5. No obvious clinical symptoms were observed in patients 1, 2, and 3. Patient 4 had severe neurological impairment and patient 5 developed Reye-like syndrome. The increasing use of MS/MS newborn screening in Japan will further clarify the clinical and genetic heterogeneity among patients with MCC deficiency in the Japanese population.

The Leu544Ile polymorphism of the growth hormone receptor gene affects the serum cholesterol levels during GH treatment in children with GH deficiency.

Objective  The cellular effects of growth hormone (GH) are mediated by the interaction between GH and the GH receptor (GHR). We investigated the association between polymorphisms in GHR and changes in height standard deviation scores (SDS), and lipid metabolism during GH treatment for GH‐deficient children.

Association study of polymorphisms in SOCS family genes with type 1 diabetes mellitus

Suppressors of cytokine signalling (SOCS) proteins play important roles in the negative regulation of cytokine signal. We first searched for polymorphisms in SOCS‐1, SOCS‐3 and SOCS‐5 genes, and examined the association of the polymorphisms with type 1 diabetes (T1D). As a result, we did not find any significant associations between SOCS genes and T1D.