Three novel COLQ mutations and variation of phenotypic expressivity due to G240X.

OBJECTIVE: To determine the molecular basis and consequences of endplate (EP) acetylcholinesterase (AChE) deficiency. BACKGROUND: The EP species AChE is an asymmetric enzyme consisting of a tail subunit composed of three collagenic strands (ColQ), each attached to a tetramer of catalytic subunits. The tail subunit is essential for insertion of AChE into the synaptic basal lamina. Human EP AChE deficiency is caused by mutations in COLQ. The authors report three novel COLQ mutations in eight kinships. METHODS: Immunocytochemistry, electron microscopy, microelectrode recordings, mutation analysis, and expression studies in COS cells were employed. RESULTS: Two mutations (275insC and Q211X) were heterozygous in one patient. EP studies in this patient revealed no EP AChE, small nerve terminals, reduced presynaptic membrane length, as well as abnormally low-evoked quantal release. The third mutation (G240X) was homozygous in six Palestinian Arab families of the same tribe and in an Iraqi Jewish patient. Expression studies of the three mutations in COS cells indicate that each abrogates formation of insertion competent asymmetric AChE. Although the three mutations have identical predicted consequences at the EP, their phenotypic expressivity varies as regards age at onset, rate of progression, and severity of symptoms. CONCLUSIONS: 1) After mutations in the AChR epsilon subunit, mutations in COLQ are emerging as second most common cause of congenital myasthenic syndromes. 2) A founder effect is likely for G240X in the Palestinian Arab families. 3) That mutations predicting total absence of AChE from the EP have variable phenotypic expressivity suggests that modifying genes or environmental factors can partially compensate for EP AChE deficiency.

Idiopathic trigeminal sensory neuropathy in childhood.

Harris first reported transient idiopathic trigeminal sensory neuropathy in 1935, although it later appeared that, in some of his patients, this condition evolved to typical chronic and painful trigeminal neuralgia. The patients who were later described by Hill and Hughes suffered a combined motor-sensory Vth cranial nerve dysfunction, and most cases reported by Spillane and Wells developed sustained permanent trigeminal neuropathy. The largest reported series of pure trigeminal sensory neuropathy includes 10 adults with varying degrees of sensory disturbance confined to all three nerve divisions. These patients experienced no facial pain or motor deficit, and 5 (50%) recovered completely within a few months. It is estimated that typical trigeminal neuralgia occurs in about 1 in 25,000 of the population and is uncommon prior to the third decade, with 1% of the cases occurring before the age of 20 years. To our knowledge, we present the first clinical report of idiopathic trigeminal sensory neuropathy occurring in childhood.

Inhibitory effect of carbamazepine on inflammatory mediators produced by stimulated glial cells.

Exposure of rat glial cells to lipopolysaccharide (LPS) induces the production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)), the inflammatory mediators implicated in the pathogenesis of seizures and epilepsy. To determine the effect of the anticonvulsant drug carbamazepine (CBZ) on the inflammatory process, LPS-stimulated rat primary glial cultures were exposed to this agent. Dose-dependent inhibition of NO and PGE(2) production was observed of up to 77 and 88%, respectively. Furthermore, a prominent (94%) decline in the secretory isoform of phospholipase A(2) (sPLA(2)) activity was found in response to CBZ and could contribute to the inhibition of PGE(2) production. Cumulatively, our findings point to the anti-inflammatory effect of CBZ on non-neuronal cells, which might, in part, contribute to its anticonvulsive effect.

Glial cells production of inflammatory mediators induced by Streptococcus pneumoniae: inhibition by pentoxifylline, low-molecular-weight heparin and dexamethasone.

Exposure of primary rat glial cells to heat inactivated Streptococcus pneumoniae, induced dose-dependent production of tumor necrosis factor alpha (TNF alpha), nitric oxide (NO) and prostaglandin E2 (PGE2). Concomitant addition of the bacterium and the synthetic glucocorticoid dexamethasone resulted in complete suppression of TNF alpha, NO and PGE2 production. Pentoxifylline, a phosphodiesterase inhibitor completely blocked TNF alpha secretion, whereas NO and PGE2 were not affected. Low-molecular-weight heparin enoxaparin caused 25-64% inhibition in TNF alpha production, up to 30% inhibition of NO secretion and a 10% reduction in PGE2. Thus, Streptococcus pneumoniae, the pathogen most commonly associated with meningitis in the Western world can be added to the list of agents causing direct stimulation of glial cells. Pentoxifylline and enoxaparin in addition to dexamethasone may limit the central nervous system local inflammatory responses and could improve the effort towards reducing the dismal outcome of patients with pneumococcal meningitis.

Subclinical status epilepticus in a child after closed head injury.

A 14-year-old girl with closed head injury and a normal computerized tomographic scan underwent an electroencephalographic tracing that surprisingly revealed typical status epilepticus electrical activity. No episodes of motor clinical convulsions were observed from the moment of trauma throughout the admission period. Treatment with phenytoin caused a dramatic clinical improvement. Repeated electroencephalogram (EEG) 4 days later was within normal limits. Posttraumatic seizures are reported after head injury, yet, the issue of "invisible" or "subclinical" seizures associated with trauma is not discussed. In these cases EEG, (an uncommon examination in the early period after head injury) may be the only tool for proper diagnosis and treatment with anticonvulsants. This case report raises the question of the role of EEG in the unconscious patients who does not present with obvious convulsions. Clinical indications for performing EEG after head trauma without seizures are discussed.

Cross-sectional and longitudinal study of the pituitary-thyroid axis in patients with thalassaemia major.

OBJECTIVE AND DESIGN: Thyroid dysfunction is known to occur frequently in thalassaemia major, but its prevalence and severity varies in different cohorts, and the long-term natural history is poorly described. We evaluated the pituitary/thyroid axis in thalassaemia major patients in a cross-sectional study and correlated abnormalities with indices of iron overload. Furthermore, the course of thyroid disease in thalassaemia major patients was assessed in a 15-year longitudinal study. PATIENTS AND MEASUREMENTS: Cross-sectional study: pituitary-thyroid axis function was examined in 37 patients (22 F, 15 M; aged 10-39 years, mean +/- SE = 21 +/- 1.4) out of a total of 43 who attended the Haematology and Endocrinology Clinics of Hadassah Hospital on a regular basis. The mean pretransfusion Hb level was 85 +/- 20 g/l, and all patients except one were treated with desferrioxamine (DF, mean +/- SE dose 20.2 +/- 2.6 mg/kg/day). Twenty-two had hypogonadotrophic hypogonadism (HH). Longitudinal study: 21 thalassaemia major patients were evaluated with TRH tests in 1976 and again in 1985. Fourteen of these and another eight were evaluated in both 1985 and 1991. RESULTS: Cross-sectional study: no patient had any clinical signs or symptoms of hypothyroidism; however, one had abnormally low T4, borderline low FT4 and normal T3 levels associated with an exaggerated TSH response to TRH consistent with mild hypothyroidism. This patient did not have a previous TRH test, but serial basal determinations over 7 years revealed a progressive decrease in thyroid function. Thirty-six patients had thyroid hormone levels within the normal range. Nine of these (24.3%) had only an exaggerated TSH response to TRH whereas seven others (19%) also had borderline elevated basal TSH levels. TSH response to TRH was not correlated with age, serum ferritin or liver function tests (ALT or GGT). Longitudinal study: mean TSH response to TRH decreased (P < 0.002), and mean T3 levels increased (P < 0.001) between 1975 and 1985. These findings are probably related to the initiation of DF treatment in 1981. During the last 6 years, four patients with previously normal TSH responses to TRH developed elevated peak TSH levels. Mean T3 concentrations decreased and TSH response to TRH increased significantly (P < 0.001 for both). CONCLUSIONS: (1) In this patient group the thyroid pituitary axis is less sensitive than the gonadal axis to iron-induced damage; only one out of 37 patients developed mild uncompensated hypothyroidism. (2) As opposed to the gonadal axis, the thyroid gland appears to fail before the central components of the axis. (3) Abnormal thyroid function may be reversible in the early stages. (4) Progression is variable, and it may take years to progress from normal to uncompensated hypothyroidism.

Gastrointestinal protein loss in children recovering from burns.

Qualitative gastrointestinal protein loss was evaluated in 10 children with second- and/or third-degree burns covering 10% or more of their body surface area (BSA) by using fecal alpha-1-antitrypsin (FA-1-AT) as a marker. Patients were subdivided according to the extent of the burned area: group I (5 patients) had burns covering less than 20% of BSA; group II (5 patients) had burns covering more than 20% of BSA (mean, 37.2% = 24.9%). Results were compared with those of 12 healthy normal controls. Mean maximal FA-1-AT excretion in group II patients (2.71 +/- 1.35 mg/g) was significantly greater than that found in group I children (0.43 +/- 0.26 mg/g; P = .006) and in the controls (0.62 +/- 0.25 mg/g; P = .004). The mean maximal FA-1-AT excretion positively correlated to the percent of BSA covered with burns (r = 0.83). Although the mean septic score (SS) of group I patients (7 +/- 2.9) was significantly greater than that calculated for group II children (3 +/- 2.45; P = .047), only 2 patients in group II had positive microbiological cultures. Patients in both groups had received more than the recommended enteral caloric and protein allowance during the 96 hours prior to the maximal FA-1-AT measurements. Within this range, no correlation was found between the amount of FA-1-AT and the number of calories per kilogram protein consumed. By using the method of FA-1-AT quantification, this study provides the first report on postburn intestinal protein loss in children.

Giardiasis with protein-losing enteropathy: diagnosis by fecal alpha 1-antitrypsin determination.

Giardia lamblia infection was documented by jejunal biopsy in a previously healthy 2-year-old boy with acute onset of hypoproteinemia due to protein-losing enteropathy. All symptoms and abnormal laboratory findings resolved with anti-Giardia therapy. This is only the second case report of giardiasis with documented protein-losing enteropathy. Further application of the fecal alpha 1-antitrypsin assay may help to clarify the relationship between Giardia infection and protein-losing enteropathy and its role in development of malnutrition.

Need for endotracheal intubation and suction in meconium-stained neonates.

In a prospective study, we determined whether routine immediate tracheal aspiration at birth is necessary in meconium-stained but otherwise normal infants delivered vaginally and having a 1-minute Apgar score greater than 8. A total of 572 newborn infants who met these criteria were randomly allocated to one of two groups. All infants underwent oropharyngeal suctioning with a DeLee catheter while the head was still on the perineum. In group I (n = 308) suctioning of the trachea under direct vision was performed instantly at birth; in group II (n = 264) this procedure was not done. There was no mortality among infants in the study, but morbidity, mainly pulmonary and laryngeal disorders, occurred in six of 308 group I infants and in none of the group II infants (P less than 0.025). Immediate tracheal suction is not a harmless intervention, and should be considered superfluous in a vigorous term neonate born with meconium-stained amniotic fluid.

Unexplained neonatal jaundice as an early diagnostic sign of septicemia in the newborn.

This prospective study was performed to determine the frequency of unexplained unconjugated hyperbilirubinemia associated with bacterial infection during the first week of life. Of 5805 infants delivered between September 1984 and December 1986, 93 jaundiced newborns without evidence of septicemia fulfilled the following criteria to be enrolled in the study: weight greater than 2500 g, gestational age greater than 38 weeks, age less than 7 days, and unexplained unconjugated bilirubin greater than 170 mumol/L (greater than 10 mg/dL) during the first 48 hours of life and/or greater than 255 mumol/L (greater than 15 mg/dL) thereafter. Evaluation for septicemia included blood and urine cultures, and white cell and thrombocyte counts. The study disclosed three (3.2%) infants who developed septicemia before any clinical suspicion had been aroused. It is concluded that bacterial infections should be considered a possible cause of neonatal unconjugated hyperbilirubinemia during the first week of life, regardless of the clinical condition of the infant.

L-deamino-8-d-arginine vasopressin treatment in pregnancy and neonatal outcome. A report of three cases.

Three women with neurohypophyseal diabetes insipidus, treated for prolonged periods, including pregnancy, with L-deamino-8-d-arginine vasopressin, gave birth in our hospital. Two of the infants had severe congenital heart disease, one of which was associated with trisomy 21. The third baby, born prematurely, presented with mild intrauterine growth retardation; at the age of 21 months, the boy had severe failure to thrive, hypotonia, and motor retardation. These three cases raise doubts as to the safety of diabetes insipidus or its treatment in pregnancy.

Functional gastrointestinal obstruction in a child with chronic granulomatous disease.

A child with chronic granulomatous disease developed an antral-pyloric obstruction, followed a month later by a postbulbar duodenal obstruction. At both areas, there was no evidence of an anatomical lesion, and some improvement in the passage of barium was observed following glucagon and metoclopramide administration. Presumably, symptoms have resulted from a functional disturbance of gastrointestinal motility.