A PIGN mutation responsible for multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) in an Israeli-Arab family.

Mutations in the PIGN gene involved in the glycosylphoshatidylinositol (GPI) anchor biosynthesis pathway cause Multiple Congenital Anomalies-Hypotonia-Seizures syndrome 1 (MCAHS1). The syndrome manifests developmental delay, hypotonia, and epilepsy, combined with multiple congenital anomalies. We report on the identification of a homozygous novel c.755A>T (p.D252V) deleterious mutation in a patient with Israeli-Arab origin with MCAHS1. The mutated PIGN caused a significant decrease of the overall GPI-anchored proteins and CD24 expression. Our results, strongly support previously published data, that partial depletion of GPI-anchored proteins is sufficient to cause severe phenotypic expression.

Small-platelet thrombocytopenia in a family with autosomal recessive inheritance pattern.

We describe the clinical and laboratory features of a family of Arab ancestry and consanguinity. Five affected individuals were diagnosed in two sibships. All affected members have small platelets, severe to moderate thrombocytopenia of neonatal onset, increased bleeding tendency and bleeding complications such as: life-threatening massive hemoperitoneum due to corpus luteum rupture during ovulation and severe mucosal bleeding. The familial involvement and early onset of the disease support the presence of a congenital genetic disorder with an autosomal recessive inheritance pattern. This does not fit the clinical spectrum of any of the currently known thrombocytopenia disorders.

Sickle cell anemia in northern Israel: screening and prevention.

BACKGROUND: Sickle cell anemia is a hemolytic anemia caused by a single mutation in position 6 of the beta globin molecule. About 80 patients with SCA in northern Israel are currently receiving treatment. OBJECTIVES: To assess a screening program in northern Israel aimed at detecting couples at risk for having offspring with SCA. METHODS: Since 1987, screening for beta thalassemia in pregnant women in northern Israel has been conducted, and from 1999 all the samples were also tested for hemoglobin S, Hgb C, Hgb D, Hgb O Arab and others. RESULTS: During the 20 year period 1987-2006 a total of 69,340 women were screened; 114 couples who carried Hgb S were detected and 187 prenatal diagnoses were performed in couples at risk for having an offspring with Hgb S. The mean gestational age was 13 +/- 4 weeks. Fifty-four of those diagnoses revealed affected fetuses and in 4 cases the couple declined to perform therapeutic abortion. CONCLUSIONS: The economic burden to the health services for treating SCA patients is about U.S.$ 7000 per year, and the institution of prevention programs has proven cost-effective in populations with a high frequency of carriers. Since our program is aimed to also detect beta thalassemia, a disease that is more frequent in this area (> 2.5%), the added cost for the prevention of SCA is less significant despite the low incidence of the S gene in our population, namely < 1%.

Response to hydroxyurea therapy in beta-thalassemia.

Although a relatively small number of previous studies suggest a modest response to hydroxyurea (HU) therapy in beta-thalassemia, more recent investigations have revealed that some transfusion-dependent patients can become transfusion-independent following HU therapy. Patients with Ggamma XmnI polymorphism, several beta-globin mutations, and alpha-thalassemia deletions were inconsistently reported to have significant responses to HU therapy. To better predict who may respond, we retrospectively evaluated the clinical response and the molecular background of 18 beta-thalassemia patients treated with HU for a mean of 46 months. The majority of transfusion-dependent patients responded to HU therapy with 9 out of 11 (82%) becoming transfusion-independent. Five thalassemia intermedia (TI) patients receiving occasional blood transfusion did not require any additional transfusions following therapy and two TI patients who had never received transfusions had a 2 g/dl increase in their hemoglobin level. The majority of beta-thalassemia major patients who became transfusion-independent (7/9) were either homozygous (5) or heterozygous (2) for the XmnI polymorphism. No correlation was identified between response to therapy and the presence of specific beta-thalassemia mutations or alpha-globin deletions. We conclude that further analysis of the degree of response of transfusion-dependent beta-thalassemia patients to HU therapy, as well as, the impact of their genetic background on this response is required to identify patients likely to have significant response.

Leishmania tropica in northern Israel: a clinical overview of an emerging focus.

BACKGROUND: In Israel, most cutaneous leishmaniasis (CL) is caused by Leishmania major. Recently a new focus of CL caused by Leishmania tropica has been described in Tiberias and the surrounding area of northern Israel. OBJECTIVE: The aim of this study was to evaluate clinical (size, number, location, and type of lesion) and laboratory (culture and polymerase chain reaction [PCR] analysis) parameters at diagnosis, response to treatment, and outcome of patients with CL due to L tropica. METHODS: Between September 2002 and March 2004, patients with direct smear-confirmed CL were evaluated; clinical records were reviewed and a telephone survey was performed. RESULTS: Forty nine patients, 34 (69%) male and 15 (31%) female, were studied. Mean age was 31.1 years (median 26 years, range 1-70); 76% of patients live in Tiberias and the surrounding area. The mean number of lesions was 2.6 (median 2, range 1-10). Lesions were commonly located on the face (61%) and upper limbs (57%). PCR analysis was performed in 27 patients and was positive for L tropica in 26. Fifty percent of patients studied received multiple therapeutic regimens because of incomplete response or treatment failure. Topical paromomycin was used in 44 patients (90%), with a complete response reported in only 17 (39%); of the 9 patients treated with intralesional sodium stibogluconate, a complete response was reported in 6 (67%); of the 5 patients treated with intravenous sodium stibogluconate, 4 (80%) were cured. LIMITATIONS: The relatively small number of patients studied combined with the fact that some were assessed retrospectively limit our conclusions. In addition, 50% of the patients studied received multiple therapeutic regimens because of failure of, or incomplete responses to, their initial therapy, thereby making comparisons difficult. CONCLUSIONS: The cure rate in those completing a course of antimony therapy, either 10 or more days of intravenous therapy or therapy administered intralesionally, was 75% (95% confidence interval [CI], 50.5-99.5%) as compared with 45% (95% CI, 28.9-60.5%) among those completing at least 10 days of topical paromomycin. To date, no standardized, simple, safe, and highly effective regimen for treating L tropica exists. Large, controlled clinical trials to evaluate current treatment regimens as well as new medications for CL, and especially CL attributed to L tropica, are urgently needed.

[The prevention programs for beta thalassemia in the Jezreel and Eiron valleys: results of fifteen years experience].

UNLABELLED: beta thalassemia is an hereditary disease caused by mutations in the beta globin gene. The clinical course is characterized by chronic hemolytic anemia that required regular blood transfusions. Secondary to the blood transfusions, patients developed severe hemosiderosis that can cause death in the early twenties unless appropriate iron chelator therapy is given. Due to the severity of the disease and the expensive treatment, a prevention program should be instituted. We report our experience in a prevention program among pregnant women in the Jezreel and Eiron Valleys during a period of fifteen years. RESULTS: A total of women were screened for beta thalassemia. Within this group, 928 were found to be carriers and 180 couples were found to be at risk to deliver an affected baby. Two hundred and fifty nine prenatal diagnoses were performed and in 45 cases the parents decided to abort the affected child. In ten cases the parents choose to deliver an affected baby. Fifteen different beta globin mutations were detected in the area covered by the program. CONCLUSIONS: A prevention program among pregnant women is feasible and prevents most of the new cases of hemoglobinopathies in the covered area. RECOMMENDATIONS: Based on our experience, and the relative low cost of this program, we recommend instituting a national prevention program for beta thalassemia throughout the country.