A patient with congenital hyperlactataemia and Leigh syndrome: an uncommon mitochondrial variant.

We report an uncommon mitochondrial variant in a baby girl with congenital hyperlactataemia and Leigh syndrome. The patient presented with a single episode of generalised clonic convulsion at day 19, and was found to have isolated and persistent hyperlactataemia ranging from 3.34 to 9.26 mmol/L. She had elevated serum lactate-to-pyruvate ratios of up to 35 and high plasma alanine concentration, indicative of a respiratory chain defect. At the age of 8 months, she developed evolving neurological and imaging features compatible with Leigh syndrome. Genetic testing for common mitochondrial DNA mutations, large mitochondrial DNA deletions, and selected nuclear genes was negative. Further analysis of lymphocyte mitochondrial DNA by sequencing revealed an uncommon heteroplasmic variant, NC_012920.1(MT-ND5):m.13094T>C (p.Val253Ala), which was previously shown to reduce complex I activity. In patients in whom there was a high suspicion of mitochondrial disorder, entire mitochondrial DNA analysis may be warranted if initial screening of common mitochondrial DNA mutations is negative.

Lactic acidosis in HIV patients receiving highly active antiretroviral therapy.

Exposure to highly active antiretroviral therapy (HAART) may lead to adverse effects related to mitochondrial toxicity such as lactic acidosis. We describe two cases of severe lactic acidosis in HIV-positive patients to illustrate the clinical symptoms and abnormal laboratory results associated with this condition. There is a lack of awareness about the risk factors for developing severe lactic acidosis and recognition of its onset with dire consequences.

Initial environment influences amphetamine-induced stereotypy: subsequently environment change has little effect.

Saline-treated and amphetamine-treated (7 mg/kg, ip, immediate) male rats from a Sprague-Dawley substrain were observed in two test environments designed to elicit different investigative responses in normal rats. Snout contact with the substrate was generated by placing the rat in a small enclosed cage. Absence of snout contact was induced by placement of the rat on a square elevated platform. Detailed ethological records were kept of locomotion, rearing, sitting, grooming, gnawing, and sleeping throughout the 90-min session. Amphetamine-treated rats incorporated environmentally contingent bodily postures into their forms of stereotyped behavior. The postures were characteristic of those evinced initially by the saline-treated rats in the same test environment. The control rats showed appropriate changes in their investigative behavior when the apparatus was changed at 10 and at 30 min postinjection. The amphetamine-treated rats, however, were completely unresponsive to such changes at 30 min and only partially so at 10 min postinjection. It was concluded that there is a temporal gradient of decreasing readiness to modify repetitive behavior after a single, large dose of amphetamine.

Dose-related response of male rats to apomorphine: snout contact in the open-field.

Apomorphine (0.01 to 5 mg/kg, SC) was administered to male rats observed singly in the open-field. The behavior of each rat was coded using a microprocessor during 3 preinjection and 9 postinjection trials of 6 min duration over a 2 hr session. The behavior categories included grooming, yawning, turning, nodding and gnawing, as well as snout contact and nonsnout contact variants of locomoting, rearing and sitting. Dose-dependent increases in the time spent in snout contact with the field surface were noted throughout the complete dose range. Both the peak and duration of the snout contact epoch increased with the dose of apomorphine. The integrated time spent in all types of snout contact proved to be the best behavioral measure for discriminating between doses of apomorphine even though the topography of snout contact response changed as a function of the dose.

p-Chlorophenylalanine and p-chloroamphetamine pretreatment of apomorphine-challenged rats: effects on solitary and social behavior.

Following an initial rise in locomotor activity, apomorphine in large doses causes a concurrent rise in brain serotonin levels, locomotor akinesia, and stereotypic gnawing. However, reports to date have failed to observe any effect of pretreatment with serotonin depletors parachlorophenylalanine (pCPA) or parachloroamphetamine (pCA) on apomorphine-induced stereotypy. In the present study the effects of pCPA (250 or 400 mg/kg i.p., 3 days) and pCA (6.4 or 10.4 mg/kg i.p., 3 days) pretreatment on apomorphine-induced (5.0 mg/kg s.c., 5 min) behavior of male rats in the open-field were compared. For half of the trials in the 78 min session, the rats were alone and for half of the trials they were paired with an untreated male rat. pCA pretreatment increased the frequency of line-crossing and of jumping, whereas pCPA pretreatment increased the duration of bouts of locomotion and gnawing. These behavioral differences may be related to the interaction of pCA and pCPA with dopaminergic subsystems in the brain.

The effect of apomorphine on the open-field behavior of rats: alone and in pairs.

Male rats were observed in the open-field while alone and while in pairs in an alternating series of trials. The trials extended over a 78 min session following injections of either saline (0.9%) or apomorphine (5.0 mg/kg, IP) into the observed member of each pair. Contrary to the literature on apomorphine stereotypy, apomorphine did not induce continuous sniffing of the environment and continuous gnawing in most rats. Sniffing of the environment remained at normal levels but there was an increase in nodding the head in the vertical plane while keeping the snout close to the floor. Apomorphine-induced hyperactivity was attributed to two factors: a sustained increase in the duration of bouts of locomotion and a failure of the frequency of bouts of locomotion to habituate to novelty. Apomorphine eliminated all social behavior directed toward the other rat, however apomorphine rats showed they were sensible to the presence of the other by increasing their locomotion and rearing when the partner was introduced.

Solitary and social behavior of male rats in the open-field.

The short-term effects of anxiolytic drugs have been assessed with tests of social affiliative behavior in rats. These tests must be completed in a brief time span, yet must include measures both of solitary activity and social behavior to dissociate affiliative from sedative and hypermotive drug effects. This study demonstrates that a paradigm of observation of alternating periods of solitary and social behavior of male rats yields data in accord with facts known about rats tested in separate, uninterrupted periods of solitary and social behavior. Agreement was obtained on the reliability of group and intersession behavior, on the levels of behavior, on the changes in behavior over trials and on the correlations between behaviors characteristic of rats tested separately in the two situations.

P-chloroamphetamine and a side-chain fluorinated analog: effects on brain amine levels and behavior.

Reserpinized (1 mg/kg, IP-24 hr) and saline-pretreated male rats were subdivided into groups receiving p-chloroamphetamine (pCA, 5.2 mg/kg, IP), 1-fluoromethyl-2-p-chlorophenylethylamine (FpCA, 5.6 mg/kg, IP), or saline, 90 minutes before the testing of behavior in the open-field and 150 minutes before sacrifice for assay of brain levels of amines. FpCA and pCA produced identical investigative and social patterns of behavior in saline pretreated animals in spite of the fact that pCA reduced serotonin levels whereas FpCA did not. Both pCA and FpCA enhanced dopamine and noradrenaline levels compared to saline controls. The behavioral syndrome common to FpCA and pCA animals was one of increased sitting still, and decreased locomotion and self-grooming while alone, and decreased locomotion, and social behavior but increased sniffing of the environment while in the company of an untreated male rat. Reserpine pretreatment exacerbated this syndrome of inactivity in pCA more than in FpCA rats even though the reserpinized groups did not differ from each other in the concentrations of the three amines.