Kinetic analysis of a new human ornithine carbamoyltransferase variant.

A new human enzymatic variant was found in a patient with ornithine carbamoyltransferase (carbamoylphosphate:L-ornithine carbamoyltransferase, EC 2.1.3.3) deficiency. This mutant enzyme has decreased affinity, with an abnormal Km value for ornithine (3-5-times greater than control at all pH values). The maximal velocity (V) varied with pH as a normal enzyme but the sigmoid curve obtained (V vs. pH) is shifted towards alkaline pH values. The pK of the functional catalytic group is 8.3 instead of 6.65 of a control enzyme. At its optimum pH the V of the mutant enzyme is greater than the V of the normal enzyme. Other mutant enzyme proteins with abnormal affinity for ornithine have already been described. They all are different from the reported here.

CoA esters of valproic acid and related metabolites are oxidized in peroxisomes through a pathway distinct from peroxisomal fatty and bile acyl-CoA beta-oxidation.

In rat liver homogenates fortified with the appropriate cofactors (ATP and CoA), valproic acid induced H2O2 production rates by far lower than those recorded on the straight medium-chain fatty acid n-octanoic acid. Using directly the CoA esters of these carboxylic acids as substrates for the rat liver H2O2-generating enzyme activities, valproyl-CoA, and n-octanoyl-CoA were found to induce similar oxidation rates. In the rat liver homogenates, cyanide-insensitive valproyl-CoA and octanoyl-CoA oxidations occurred at rates similar to those of valproyl-CoA and octanoyl-CoA oxidase(s), respectively. Studies on fractions obtained from rat liver postnuclear supernatants by isopycnic centrifugation on a linear sucrose density gradient disclose that the density distribution of valproyl-CoA oxidase superimposes to those of catalase, fatty acyl-CoA oxidase and cyanide-insensitive fatty acyl-CoA oxidation, three peroxisomal marker activities. By contrast, the cyanide-insensitive valproyl-CoA oxidation does not adopt the typical peroxisomal distribution of these activities but rather exhibits a mitochondrial localization with, however, a minor peroxisomal component. Interestingly enough, the comparative study of rat tissue distribution, inducibility by clofibrate and sensitivity to deoxycholate indicated that valproyl-CoA oxidase is an enzyme distinct from fatty acyl-CoA oxidase and bile acyl-CoA oxidase. Taken as a whole, the results presented here support the occurrence of a peroxisomal oxidation of the CoA ester of valproic acid and its delta 4-enoic derivate which might be characterized by two major features: initiation by an acyl-CoA oxidase distinct from fatty and bile acyl-CoA oxidases, and inability to complete the beta-oxidation cycle which would not proceed, at significant rates, further than the beta-hydroxyacyl-CoA dehydrogenation step in peroxisomes.

Synthesis and anticonvulsant activity of two N-(2,6- dimethylphenyl)pyridinedicarboximides.

Two N-(2,6-dimethylphenyl)pyridinedicarboximides were synthesized and evaluated for anticonvulsant properties and neurotoxicity. These compounds were mainly active against maximal electroshock (MES) induced seizures in animal models. In rats dosed orally, N-(2,6-dimethylphenyl-2,3-pyridinedicarboximide 1 exhibited an anti-MES ED50 of 54.2 mumol/kg and a protective index (PI = TD50/ED50) superior to 27.4. In mice dosed intraperitoneally, compound 1 is less active against MES induced seizure (ED50 = 160.9 mumol/kg) and more neurotoxic as evidenced by a low protective index (1.93). Comparison with published data on phenytoin reveals that compound 1 is, in rats dosed orally, two-fold more potent than this antiepileptic drug against MES induced seizures.

Anticonvulsant activity of some 4-amino-N-phenylphthalimides and N-(3-amino-2-methylphenyl)phthalimides.

A series of fifteen N-phenylphthalimides including 12 4-amino-N-phenylphthalimides and three N-(3-amino-2-methylphenyl)phthalimides was prepared and evaluated for anticonvulsant properties. The compounds were tested against seizures induced by electroshock (MES) and pentylenetetrazol (scPTZ) in mice dosed intraperitoneally. Their neurologic toxicity was assessed using the rotorod assay procedure. The most potent 4-amino-N-phenylphthalimides against MES were those possessing small lipophilic groups in either 2 or 2 and 6 positions of the N-phenyl ring. They also exhibited some activity against scPTZ and were the most toxic of the series. By contrast, no activity against scPTZ or neurotoxicity could be observed up to 300 mg/kg for members of the N-(3-amino-2- methylphenyl)phthalimide series. In this series, the order of anti-MES activity appears to correspond to the phthalimide ring substitution pattern of 4-amino > H > 4-methyl. Quantitation of anticonvulsant properties and toxicity of 4-amino-N-(2,6-dimethylphenyl)phthalimide (ADD 213063) previously initiated in rats has been, here, extended to mice dosed intraperitoneally but also orally. The confrontation of the two modes of administration in mice suggests that ADD 213063 presents with a good bioavailability.

[Globoid cell leucodystrophy (Krabbe's disease). Peripheral nerve lesion (author's transl)]. / Leucodystrophie à cellules globoïdes (maladie de Krabbe). Lésions nerveuses périphériques

Morphological study of peripheral nerves in two patients with globoid cell leucodystrophy (Krabbe's disease) demonstrates: 1degree segmentary demyelination; 2degrees marked loss of large (8-10 micra) myelinated fibres; 3degrees significant increase of the mean transverse fascicular area by proliferating collagen fibres; 4degrees electron-microscopic signs of remyelination with small onion-bulb formations. These findings can explain clinical features such as the disappearance of the deep tendon reflexes, the gradual transition of hypertonia into combined hypertonia-hypotonia and the concomitant slowing of nerve conduction velocity. The ultrastructural study reveals the presence of large and small inclusions which are either located within lysosomes or free in the cytoplasm of Schwann cells and fibroblasts. The inclusions are probably consequences of the disturbed metabolism of cerebrosides. Their appearance is sufficiently specific in order to allow a diagnosis of Krabbe's disease.

[Prolonged remission in subacute sclerosing panencephalitis: 2 cases]. / Rémissions prolongées dans la panencéphalite sclérosante subaigue: 2 cas.

Long survival in subacute sclerosing panencephalitis (SSPE), including total disappearance of clinical signs, is rare. Two cases are reported. They concern a girl and a boy who, at age 13 and 15, developed SSPE and are still in remission 6 and 5 years later. After a typical onset and course over periods of 12 and 18 months, clinical improvement was observed and periodic EEG complexes disappeared. However, the electrophoretic oligoclonal pattern of CSF proteins and the elevated measles titers persisted (in one case specific CSF IgM were still increased 6 years after the onset). MRI showed asymmetrical areas of high-intensity signal in both white and gray matter, predominant in the temporal, parietal and occipital regions. The age at which SSPE begins and the interval between measles and SSPE onset are not prognostic factors. On the other hand, in reported cases with lasting remission SSPE did not progress beyond Jabbour's stage II. The second typical feature of these long-term improvements is disappearance of EEG periodic complexes and emergence of a normal basic background activity. No other prognostic factor has been reported.

[Celiac disease, cerebral calcifications and epilepsy syndrome]. / Le syndrome maladie coeliaque, calcifications cérébrales et épilepsie.

The syndrome of coeliac disease, epilepsy and cerebral calcifications is a rare complication of coeliac disease. The pathological changes consist in a patchy pial angiomatosis and resemble those of Sturge-Weber syndrome, whose variant without port-wine angioma must be ruled out. Typical course includes three stages leading to a severe encephalopathy. However, the mental impairment is extremely variable. The pathogenetic process is so for unknown; main clues involve a chronic folic acid deficiency or a HLA-related autoimmune disorder. Treatment requires early gluten-free diet and anti-epileptic drug.

[Benign reflex myoclonic epilepsy in infants]. / L'épilepsie myoclonique bénigne réflexe du nourrisson.

BACKGROUND: Myoclonic epilepsy of infancy are seldom benign. CASE REPORT: A 25-month old girl developed myoclonic jerks either spontaneously either as reflex responses to auditory and tactile stimuli, such as sudden touching of the face or trunk from the age of 4 months. The jerks disappeared after valproate therapy. Neurological examination was normal with a follow-up of 9 months. CONCLUSION: This condition resembles that described in 1995 by Ricci et al. In must be differentiated from other myoclonic epilepsies of infancy, reflex epilepsies and hyperekplexia. It could be the earliest from of idiopathic generalized epilepsy.

[Holoprosencephaly with neurogenic hypernatremia]. / Holoprosencéphalie avec hypernatrémie neurogène.

BACKGROUND: Semi-lobar holoprosencephalies can be seldom complicated by neurogenic hypernatremia, which must be distinguished from other causes of hypernatremia. CASE REPORT: In two admitted children with semi-lobar holoprosencephaly, 7 months and 4 years old, biological data revealed chronic hypernatremia and hyperosmolarity without clinical signs of dehydration, which were finally attributed to a neurogenic hypernatremia. CONCLUSION: Neurogenic hypernatremia must be clearly differentiated from other causes of hypernatremia since it never causes specific complications.

[Brain abscess complicating dental caries in children]. / Abcès cérébraux de l'enfant compliquant des caries dentaires.

Brain abscess following dental or periapical infection is rare in childhood. This report describes brain abscesses found in two children with dental caries. Case 1.--A 12 year-old boy was admitted because he had suffered from acute meningitis for 3 days. Clinical examination showed symptoms of meningitis plus palsy of the right third and fourth cranial nerves and of the left facial nerve, and a defect in the left temporal field. Funduscopic examination showed papilledema; CT scan and MRI showed a ring-shaped lesion in the right occipital area. The patient was given cefotaxime and thiamphenicol. The abscess was drained; bacteriological examination showed Actinomyces viscosus and Peptostreptococcus magnus. The neurological condition and the CT scan lesion improved, but intracranial pressure increased again on the 17th day after the onset, requiring replacement of the antibiotics by rifampicin and ampicillin plus clavulanic acid for 2 months. This brain abscess appeared to be metastatic, derived from the infection of a large dental cyst due to a dental infection that had been treated 6 months earlier. Case 2.--A 8 1/2 year-old girl was admitted because she was suffering from palsy of the left facial nerve and left arm. She had had headaches and fever for a few days. Clinical examination showed the palsies and drowsiness. CT scan showed two brain abscesses. The patient was given ceftriaxone, fosfocin and metronidazole. She had been treated for a gingival abscess 1 month earlier, and had two infected teeth extracted. Improvement of the intracranial pressure was transient and the antibiotics were changed on the 12th day of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

[Acute respiratory insufficiency revealing myasthenia gravis: apropos of 3 cases]. / Insuffisance respiratoire aiguë révélatrice d'une myasthénie juvénile: à propos de trois cas.

BACKGROUND: Myasthenia gravis is usually revealed by a ptosis or a diplopia. A respiratory muscle weakness often occurs during the course but an acute respiratory failure as initial feature is unusual. CASE REPORTS: Three girls, aged 8, 10 and 14 years, were hospitalised in an intensive care unit, along a 15 year-period, for an acute respiratory distress. The first two children suffered from skeletal and bulbar muscle weakness. The third, admitted with the diagnosis of unexplained pneumonia, was complaining of skeletal and bulbar muscle weakness for the last 18 months. Myasthenia gravis was confirmed with electromyography, and detection of the acetylcholine-receptors antibodies in all three cases. CONCLUSION: Any unexplained acute respiratory distress must lead to search for skeletal and bulbar muscle weakness, specially after muscular exercise or at the end of day, manifestations which characterize myasthenia gravis.

[Perforating milia-like idiopathic calcinosis of the extremities in Down syndrome]. / Calcinose miliaire idiopathique perforante des extrêmités chez une malade trisomique 21.

INTRODUCTION: Several skin diseases can be seen in patients with trisomy 21. We report a case of miliary calcinosis of the extremities. CASE REPORT: A 15-year old adolescent with Down's syndrome presented small papular miliary lesions which had developed over 18 months and tended to discharge a chalk-like substance via the epidermis. Approximately 15 lesions were present on the hands and feet. Histologically, there was a well-delimited calcium deposit in the superficial dermis. There was no alteration in phosphorus/calcium metabolism. Brain CT-scan and cardiac echography did not reveal any calcifications. DISCUSSION: Miliary calcinosis cutis may not be exceptional in Down's syndrome, although only 9 observations have been reported. Preferential localizations include the hands, wrists and feet. Association with syringoma has been noted but would appear to be fortuitous. Transepidermal elimination of the calcium deposits is frequent. Pathogenic hypotheses include precipitation of calcium salts in sudation products and/or increased synthesis by fibroblasts. The association with trisomy 21 appears to be significant since only three cases have been reported in patients with normal karyotypes. This entity should be individualized as perforating milia-like idiopathic calcinosis cutis of the extremities.

Synthesis and anticonvulsant activity of some N-phenylphthalimides.

The anticonvulsant potential of a series of N-phenylphthalimide derivatives has been screened in subcutaneous pentylenetetrazole seizure (scPTZ) and maximal electroshock seizure (MES) tests. Intraperitoneal 4-amino-N-phenylphthalimides were the most potent agents against MES in mice. Referring to the N-(2,6-dimethyl-phenyl)phthalimide structure, the order of anticonvulsant activity appears to correspond to the phthalimide ring substitution pattern of 4-amino > 4-nitro > 4-methyl; H > 3-nitro; 3-amino. The 4-amino-N-(2-methylphenyl)-phthalimide displays an anti-MES ED50 of 47.61 mumol/kg with a protective index (PI) of 4.2. Oral administration to rats of the compounds found to be active in mice showed that the 4-amino-N-(2,6-dimethylphenyl)phthalimide is the most potent anti-MES agent in rats, exhibiting an ED50 of 25.2 mumol/kg and a PI greater than 75. Regarding the nature of the 2 and 6 substituents of the N-phenyl ring, the anticonvulsant efficiencies may be ordered as follows: 2,6-dimethyl > 2-methyl > 2-ethyl > 2-ethyl-6-methyl > 2,6-diethyl > unsubstituted phenyl ring. N-Phenylphthalimide derivatives seem to have great potential as candidate anticonvulsant drugs.

[Pathogenetic left tracheal bronchus. A review of the literature in connection with four cases (author's transl)]. / La bronche "trachéale" gauche pathogéne. Revue de la littérature à propos de 4 observations.

The so-called left "tracheal" bronchus is usually found to be a transposition of the segmental apicoposterior bronchus of the upper left lobe onto the terminal portion of the main trunk. This systematisation abnormality is less common on the left than on the right. In our experience, based on 1,500 bronchographs carried out on adults and children, we have discovered seven left "tracheal" bronchi four of them associated with an obstructive emphysema in the same area. Although this malformation is rarely encountered in the etiologies of interlobular or poly-segmental emphysemas in children, it does however appear that an upper left emphysema has two etiologies which are peculiar to it: segmental bronchial atresia and left "tracheal" bronchi. Why the left "tracheal" bronchi is more often pathogenetic in comparison with the right is open to speculation. As in many other examples of tracheo-bronchial compression for vascular reasons, the close contact between the hyperarterial ectopic bronchi and the left pulmonary artery seems, logically, to be the culprit.