Clinical course of patients with WASP gene mutations.

Mutations of the Wiskott-Aldrich syndrome protein (WASP) gene result either in the classic Wiskott-Aldrich syndrome (WAS) or in a less severe form, X-linked thrombocytopenia (XLT). A phenotype-genotype correlation has been reported by some but not by other investigators. In this study, we characterized WASP gene mutations in 50 Japanese patients and analyzed the clinical phenotype and course of each. All patients with missense mutations were WASP-positive. In contrast, patients with nonsense mutations, large deletions, small deletions, and small insertions were WASP-negative. Patients with splice anomalies were either WASP-positive or WASP-negative. The clinical phenotype of each patient was correlated with the presence or absence of WASP. Lack of WASP expression was associated with susceptibility to bacterial, viral, fungal, and Pneumocystis carinii infections and with severe eczema, intestinal hemorrhage, death from intracranial bleeding, and malignancies. Rates for overall survival and survival without intracranial hemorrhage or other serious complications were significantly lower in WASP-negative patients. This analysis provides evidence for a strong phenotype-genotype correlation and demonstrates that WAS protein expression is a useful tool for predicting long-term prognosis for patients with WAS/XLT. Based on data presented here, hematopoietic stem cell transplantation should be considered, especially for WASP-negative patients, while the patients are young to improve prognosis.

High-dose immunoglobulin therapy for Guillain-Barré syndrome in Japanese children.

BACKGROUND: Guillain-Barré syndrome (GBS) is an acute acquired demyelinating polyneuropathy, presumed to be immune-mediated. Intravenous immunoglobulin (IVIg) has been used to treat GBS and was found to be effective. However, a well-controlled study of pediatric GBS has not been conducted in Japan. Therefore, to evaluate the efficacy of IVIg in the treatment of GBS, an open-labeled study was performed in pediatric patients. METHODS: Participants in the study were required to be younger than 15 years old, and diagnosed as having moderate or severe GBS. IVIg (400 mg/kg per day) was administered to patients for five consecutive days. Predefined outcome measures were defined on a seven-point scale of motor function (Hughes' functional grade [FG]). RESULTS: Eleven patients were treated with IVIg. The median time taken to improve by one grade on the FG scale was 10.0 days after initial treatment. Two weeks after initial treatment, 72.7% of patients treated with IVIg improved by one or more grades, and 36.4% improved by two or more grades, measured on the FG scale. After 4 weeks an improvement by one or more grades was observed in 81.8% of patients, and two or more grades in 63.6% of patients. These improvement rates were markedly greater than would occur with the natural course of GBS1. Adverse events (subjective symptoms or abnormal laboratory findings) were observed in four patients, although all were temporary and mild. CONCLUSIONS: The authors conclude that IVIg is a safe and effective treatment for childhood GBS, which shortens the time to recovery.

Genetic analysis of Japanese patients with 21-hydroxylase deficiency: identification of a patient with a new mutation of a homozygous deletion of adenine at codon 246 and patients without demonstrable mutations within the structural gene for CYP21.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is one of the most common inherited metabolic diseases. We studied 52 Japanese 21-hydroxylase deficiency patients corresponding to 49 families (98 chromosomes) to detect the mutations in 21-hydroxylase genes using Southern blotting, PCR-restriction fragment length polymorphism, and a direct sequencing method. Among the 52 patients (49 families), 35 patients (33 families) were diagnosed as the salt-wasting type, 12 (12 families) as the simple virilizing type, and 5 (4 families) as the nonclassical type. Our findings were as follows. 1) The complete genotype that had homozygous or compound heterozygous mutations was determined in 43 of 49 families (87.8%). Among the remaining patients, no mutation was found in the structural gene of either allele in 3 cases, and a mutation was detected in only 1 allele in 3 cases. This means that at least 9 of 98 alleles have some unusual mutations or recombinations that we cannot detect by our method or gene defects outside of the structural gene. 2) Although the common mutation of Caucasian nonclassical patients is V281L, none of our 4 nonclassical families showed this mutation, and 3 of them had the P30L mutation at least on 1 allele. 3) We identified a putative new mutation, homozygous deletion of adenine at codon 246, in a salt-wasting patient. Although we have not analyzed the functional consequence of this mutation, it causes substitution noncoding for Met(256) in exon 7 and premature termination of the mRNA before the heme-binding region of the P450 polypeptide, which would result in a completely nonfunctional enzyme.