Yoshitomo Sawada

Neopterin and biopterin concentrations in cerebrospinal fluid in controls less than 1 year old.

Neopterin and biopterin concentrations were measured in cerebrospinal fluid (CSF) and urine samples from controls less than 1 year old. This is the first time for CSF reference data for controls less than 1 year old to be reported. The ratio of neopterin to biopterin in CSF 0-30 days (n = 48) of age in control samples was 0.65 +/- 0.31 (SD), which was far lower than that in urine over the same time period, 4.0 +/- 1.9 (SD), (n = 51). This finding is very important when diagnosing 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency and peripheral form of PTPS deficiency in the neonatal period. Our CSF reference data for controls should be useful in the diagnosis of PTPS deficiency.

Diagnosis and treatment of 6-pyruvoyl-tetrahydropterin synthase deficiency

We detected a case of 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency during a neonatal mass screening and considered the differentiation and treatment of the peripheral form of PTPS deficiency. Although single treatment of BH4 had been started, because of the lowered biopterin (B) value, elevated neopterin (N) value, and N/B ratio in the cerebrospinal fluid (CSF), the peripheral form was judged negative and combined treatment with L-dopa and 5-hydroxy tryptophan (5-HTP) was started. Follow-up study will be necessary to confirm the diagnosis of PTPS deficiency.

Experimental Research on a New Treatment for Maternal Phenylketonuria(PKU)

More girls with phenylketonuria (PKU) enter childbearing ages, and most such women are mentally normal, having been born since newborn screening was initiated in the 1970s and treated from early infancy with a low phenylalanine (Phe) diet. Women with PKU not treated prior to conception can have a pregnancy that results in serious fetal damage1. Maternal PKU as a cause of mental retardation and birth defects is a new phenomenon. There will be an increased need for specific therapies in maternal PKU. Low Phe diet is essential for the treatment of maternal PKU. It should be started before pregnancy and it is necessary to maintain their plasma Phe levels around 5 mg/dl throughout their pregnancy2. However they are usually controlled around 10 mg/dl because of the difficulty of the diet therapy. We made an animal model of maternal PKU by the intravenous injection of Phe to pregnant guinea-pigs, and examined plasma, liver and brain Phe levels in their fetuses after an intravenous administration of 6R-5,6,7,8-tetrahydrobiopterin (R-BH4) to the mothers.

TETRAHYDROBIOPTERIN RESPONSIVE HYPERPHENYLALANINEMIA WITHOUT BIOPTERIN DEFICIENCY

Hyperphenylalaninemia (HPA) results from a deficiency of the enzyme phenylalanine hydroxylase (PAH) or of its cofactor, tetrahydrobiopterin (BH4). In 1999, Kure et al reported that some patients with PAH deficiency showed lowering of blood Phe levels after BH4 loading (1). We found several patients with HPA whose serum phenylalanine levels decreased at 24 hours after loading with BH4 (2). We reexamined some patients with HPA discovered by screening for phenylketonuria (PKU) and reevaluated the response of BH4 loading test.

Neopterin in Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis (SSPE) has a very poor prognosis. In recent years, the introduction of various treatments including inosiplex and interferon has somewhat improved the survival rate1,2. However, there are large variations in the response of patients. It is difficult to forecast the response and prognosis on the basis of clinical symptoms alone, but sequential recordings by computed tomography (CT) and magnetic resonance imaging (MRI) can be used to identify the lesions and severity of the disease, providing information that may be correlated with changes in the neurological symptoms3. A number of laboratory tests have been used to define the clinical stage of patients with SSPE. Here, we report that sequential monitoring of neopterin, ferritin, and creatine kinase (CK) in the cerebrospinal fluid (CSF) of two patients with SSPE was useful as an index of the progress of the disease.

The Effect of Tetrahydrobiopterin (BH4) on Sperm Motility

Seminal plasma has the highest concentration of tetrahydrobiopterin (BH4) in human body fluids. This study evaluated the effect of BH4 in the seminal plasma on sperm motility.

The Effect of Tetrahydrobiopterin (BH4) on Diabetic Nephropathy in Streptozotocin (STZ) Induced Diabetic Rats

Nitric oxide synthase (NOS) requires tetrahydrobiopterin (BH4) as a coenzyme. Recent works showed that NOS activity is regulated in a BH4-dependent manner. In this study we examined antinephropathic effects of BH4 in streptozotocin (STZ) induced diabetic rats.

Experimental Research on a Fetal Treatment for Tetrahydrobiopterin Deficiency

Tetrahydrobiopterin (BH4) synthase deficiency has a high incidence of low birth weight,1 and some of them had a mild mental retardation in spite of their early treatment2. In this study we performed an intravenous loading of 2,4-diamino-6-hydroxypyrimidine (DAHP) with a small amount of BHU, and successfully made a model of fetal BH4 deficiency. We investigated the possibility of the fetal therapy of BH4 deficiency in this model by measurements of phenylalanine(Phe), tyrosine(Tyr), BH4, dopamine and catecholamines.

Oral administration of liposomally entrapped tetrahydrobiopterin.

Tetrahydrobiopterin (BH4) has been used for the therapy of BH4-deficient patients. However, BH4 is poorly absorbed from the intestine. The plasma level of biopterin that was reached after oral administration of BH4 to a BH4-deficient patient was reported to be 1–2% of the levels reached after either intravenous or subcutaneous administration1. This poor absorption from the intestine needs a large amount of BH4 for the oral therapy, leading to high costs.

New Pteridine Assay System Using Automated Sequential Trace Enrichment of Dialysates

Since Niederwieser et al. reported the biopterin deficiency in 1979, pteridine analysis has been essential for the diagnosis and treatment of tetrahydrobiopterin deficiency. Recently the importance of pteridine in human body fluids have been recognized and pteridine analysis has been used for a clinical marker not only in hyperphenylalaninemia but also in other diseases such as cancer, AIDS, dystonia and so on. Therefore in near future it will become a routine laboratory examination. Fukushima-Nixons method has been most commonly used for pteridine assay, but preparation of biological samples prior to high performance liquid chromatography analysis has always been a time-consuming process.