A new mutation in a family with cold-aggravated myotonia disrupts Na(+) channel inactivation.

OBJECTIVE: To identify the molecular and physiologic abnormality in familial myotonia with cold sensitivity, hypertrophy, and no weakness. BACKGROUND: Sodium channel mutations were previously identified as the cause of several allelic disorders with varying combinations of myotonia and periodic paralysis. A three-generation family with dominant myotonia aggravated by cooling, but no weakness, was screened for mutations in the skeletal muscle sodium channel alpha-subunit gene (SCN4A). METHODS: Single-strand conformation polymorphism was used to screen all 24 exons of SCN4A and abnormal conformers were sequenced to confirm the presence of mutations. The functional consequence of a SCN4A mutation was explored by recording sodium currents from human embryonic kidney cells transiently transfected with an expression construct that was mutated to reproduce the genetic defect. RESULTS: A three-generation Italian family with myotonia is presented, in which a novel SCN4A mutation (leucine 266 substituted by valine, L266V) is identified. This change removes only a single methylene group from the 1,836-amino-acid protein, and is present in a region of the protein previously not known to be critical for channel function (domain I transmembrane segment 5). Electrophysiologic studies of the L266V mutation showed defects in fast inactivation, consistent with other disease-causing SCN4A mutations studied to date. Slow inactivation was not impaired. CONCLUSIONS: This novel mutation of the sodium channel indicates that a single carbon change in a transmembrane alpha-helix of domain I can alter channel inactivation and cause cold-sensitive myotonia.

Autologous bone marrow transplantation for childhood acute lymphoblastic leukemia in remission: first choice for isolated extramedullary relapse?

Between May 1984 and May 1992, 75 children 3-19 (median 9) years of age underwent autologous marrow transplant. Clinical data were obtained from the BMT Registry of the AIEOP (Italian Association of Pediatric Hemato/Oncology). Fifty-six children were transplanted after marrow +/- other site(s) relapse and 19 after an isolated extramedullary relapse. The transplant preparative regimens varied according to the center performing the transplant. Seven patients (9%) died of transplant-related complications. Forty-four (58.6%) of 75 patients relapsed again following autologous BMT. The 5-year DFS was 27.8%. An isolated extramedullary relapse was the only variable that statistically influenced DFS. In this retrospective study, autologous BMT for patients with ALL in second CR following marrow relapse did not offer an encouraging result (13% probability of DFS at 5 years), whereas autologous BMT following an (early) isolated extramedullary relapse resulted in nearly 70% DFS. Autologous BMT may be appropriate for this latter group of patients.

ABMT for early isolated extramedullary relapse of childhood ALL.

From July 1987 to July 1991, 12 children underwent AMBT following high-dose cytarabine (HD Ara-C) plus 14.4 Gy hyperfractionated total body irradiation (hyfr-TBI) for early isolated extramedullary relapse of ALL, while in first BM remission. No patient received intrathecal prophylaxis following AMBT. One patient died on day +5 due to sepsis and three patients, two of them transplanted in second and third CNS relapse, respectively, died from BM relapse occurring 1.5, 4 and 5 months after AMBT. Eight of the 12 survive disease-free with a median follow-up of 24 months (range 14-62 months). The toxicity of HD Ara-C plus hyfr-TBI was acceptable and well controlled with supportive therapy. These results suggest that ABMT following HD Ara-C plus hyfr-TBI may eradicate leukemia from extramedullary sites of ALL relapse.

Autologous bone marrow transplantation in secondary acute monoblastic leukemia following Hodgkin's disease.

Acute non lymphocytic leukemia (AnLL) is the most common second malignancy (SM) in survivors of childhood Hodgkin's Disease (HD). Chemotherapy responsiveness is usually poor and death ensues briefly after diagnosis. We report the case of a 13 year-old girl, affected by HD, stage IV, mixed cellularity, who developed AnLL one year after the HD treatment was stopped. Autologous Bone Marrow Transplantation (ABMT) was performed 9 months after complete remission (CR) was achieved by chemotherapy. Presently, the patient is alive and on continues CR, 3 years and 7 months after ABMT. ABMT may be a promising approach for secondary AnLL, the prognosis of which is almost invariably fatal with conventional chemotherapy.

Autologous bone marrow transplantation for acute lymphoblastic leukemia: the high dose vincristine study of AIEOP BMT group.

This study was performed in 5 pediatric centers. It considered a group of children affected by acute lymphoblastic leukemia (ALL) treated with ABMT. 56 patients were considered, 35 males and 21 females, with a median age of 11 years. The children were transplanted in 2nd (36) or subsequent (20) complete remission. The mean of 1st remission duration was 32 months. Analysis of the sites of relapse before transplantation showed that 39 patients had bone marrow relapses, 17 patients had CNS and/or testicular isolated relapses only. 32 harvests were purged in vitro by 1 mcgr/ml Vincristine and 30 mcgr/ml Prednisone, 16 by 100 mcgr/ml Mafosfamide, 8 were not cleaned. 29 patients received high dose Vincristine (4 mg/m2), TBI (1200 cGy), Cyclophosphamide (3600 mg/m2) as standard conditioning regimen before transplant. 27 patients received other conditioning treatments with (14) or without (13) TBI. Of the 56 children 25 relapsed from 1 to 42 months after ABMT, 7 toxicity related deaths were registered and 1 death for second tumor was observed. 23 children remained in continuous complete remission from 1 to 49 months after transplantation. The probability of EFS at 4 years was 21%. High dose Vincristine did not statistically improve the EFS, but a trend was observed (44% versus 0%). Vincristine, Asta-Z or none purging did not show any significant effect on EFS (37% vs 32% vs 0%). On the contrary when the EFS was related to the site of relapse, isolated or sistemic, the difference was almost statistically significant (46% vs 18%). The analysis of our results indicates the isolated relapse as good prognostic factor in ABMT for ALL and high dose Vincristine associated to conditioning regimen as worthy of further investigations.

Undifferentiated (embryonal) sarcoma of the liver in childhood: results of a retrospective Italian study.

The clinical features and the treatment of undifferentiated (embryonal) sarcoma of the liver in 8 patients younger than 19 years old were analyzed. All these cases were registered in the retrospective multicentric study on childhood malignant tumors of the liver, conducted between 1983 and 1985 by the Italian Association of Pediatric Hematology Oncology. The age of the patients ranged from 94 to 190 months (median = 113.5 months); all children were males. An abdominal mass was the common presenting features. Abnormalities in hemogram and common liver tests were rarely reported. Angiography revealed various degrees of vascularization in these tumors. Two patients achieved a surgical complete remission (CR) at diagnosis; one patient achieved surgical CR after primary chemotherapy with vincristine, adriamycin, cyclophosphamide and 5-fluorouracil, which reduced the tumor volume and permitted surgical resection. Two of these patients are still in CR at 14 and 60 months after diagnosis; the third patient died of liver failure without evidence of recurrence 6 months after diagnosis. All of the other patients, who never achieved CR, died of disease. One was lost to follow-up, and one surgical death occurred. Reports of childhood undifferentiated sarcoma are reviewed.

Impairment of polymorphonuclear leucocyte function during therapy with synthetic ACTH in children affected by epileptic encephalopathies.

Therapy with synthetic ACTH (zinc tetracosactide) in children affected by epileptic encephalopathy is often associated with a large number of infectious complications. We studied the phagocytic activity of polymorphonuclear leucocytes (PMN) in 9 children with West or Lennox-Gastaut syndrome, measuring PMN superoxide anion production during the phagocytosis of particles of Zymosan and after phorbol myristate acetate (PMA) stimulation. The test was performed before, during and after therapy with zinc tetracosactide (0.02 mg/kg/day for 15 days). At the same time plasma immunoglobulins, C3, C4, C3 activator and cortisol were determined. During treatment PMN phagocytic function was significantly reduced but returned to normal levels after suspension of therapy. The other hematological parameters considered remained within the normal range. During the follow-up of the patients we observed 15 infectious episodes (3 mucocutaneous candidiasis, 2 enterocolitis, 4 urinary tract infections, 1 otitis media, 3 bronchiolitis, 2 pneumonia). One of the patients died of a bilateral pneumonia. Three children were treated with ACTH on alternating days. In these patients PMN phagocytic activity was less impaired and 2 infectious episodes rapidly resolved. Alternate day ACTH therapy seems to be preferable.

[Late recurrence of Wilms' tumor]. / Recidiva tardiva di tumore di Wilms.

We present a patient with a Wilms' Tumor recurring after 7 years from the primitive surgical excision. After the relapse, surgery and conventional chemotherapy (with Actinomycin-D, Cyclophosphamide and Vincristine) permitted to achieve a second complete remission. Now the patient is alive without evidence of disease after 4 years from the relapse. The non-complete surgical excision of the tumor and the particular biological activity of the residual cells could explain the late relapse.

[Prolonged remission of infectious symptoms during treatment with ascorbate in a case of Chediak-Higashi syndrome]. / Prolungata remissione della sintomatologia infettiva durante il trattamento con ascorbato in un caso di sindrome di Chediak-Higashi.

A case of Chédiak-Higashi syndrome in a 12-years old girl is presented. The Authors refer recent advances in the pathogenetic mechanism and in the treatment of this syndrome. Furthermore, they report a prolonged remission of infections during ascorbic acid therapy.

[Cerebral changes shown by computed tomography in children with acute lymphatic leukemia after therapy]. / Alterazioni cerebrali riscontrate con TC in bambini affetti da leucemia linfatica acuta fuori terapia.

The authors discuss the CT findings of the late brain damage by the radiochemotherapic treatment for the prophylaxis of meningeal leukemia in 50 patients, 1 divided by 15 years old. The more frequent CT findings are: enlargement of the subaracnoid spaces; ventricular dilatation; hypodensity of cerebral parenchima; calcifications. These findings correspond to two clinical and anatomo-pathological conditions: subacute leucoencephalopathy and mineralizing microangiopathy. A greater damage on central nervous system was demonstrated in younger children (5 years old) at the time of prophylaxis of meningeal leukemia, that were irradiated with NSD = 950 ret.

Inhibitory effects of bilirubin and photobilirubin on neonatal and adult T lymphocytes and granulocytes.

The lymphoproliferative response to phytohemagglutinin of lymphocytes and spontaneous motility, chemotaxis and phagocytic activity of granulocytes were studied in the newborn and adult blood in the presence of bilirubin and photobilirubin. All of these activities were inhibited to the same extent by these substances. In addition, a significant difference between newborn and adult values was found. In conclusion, the authors suggest that phototherapy does not decrease bilirubin cellular toxicity.