Clinical manifestations of mitochondrial DNA depletion.

OBJECTIVE: We studied five new patients with mitochondrial DNA (mtDNA) depletion to better define the clinical spectrum of this disorder. BACKGROUND: mtDNA depletion has been associated with myopathy or hepatopathy, or both, in infants and young children. Involvement of the CNS and peripheral nervous system has not been clearly established. METHODS: We reviewed the clinical course and performed morphologic, biochemical, and genetic analyses of muscle samples from five patients. RESULTS: Age at onset ranged from 3 months to 5 years, and one patient survived until age 10 1/2 years. Two patients had laboratory and clinical features reminiscent of dystrophinopathy, two had evidence of brain involvement, and two had peripheral neuropathy. Muscle biopsy specimens in all patients showed abundant ragged-red fibers. Biochemistry showed cytochrome c oxidase deficiency in all patients tested and decreased activities of other respiratory chain complexes in some. CONCLUSIONS: Inheritance appeared to be autosomal recessive, suggesting that mutations in nuclear DNA are responsible for mtDNA depletion. mtDNA depletion should be considered in children with mitochondrial disorders of uncertain etiology, and criteria for diagnosis are proposed.

Alpha-adrenergic stimulation of growth hormone release in perifused rat anterior pituitary reaggregate cell cultures.

It has been previously shown that beta-adrenergic agonists stimulate growth hormone (GH) release from perifused rat anterior pituitary cell aggregates cultured in serum-free defined medium for 5-6 days. The present data show that the natural beta-agonist epinephrine (EPI) stimulates GH release through an additional alpha-adrenergic mechanism. The involvement of this mechanism was suggested by the following findings. The intrinsic activity of EPI, at concentrations greater than 10 nM, was significantly higher than that of isoproterenol (ISO) in stimulating GH release. Phenylephrine (PHE), a specific agonist of alpha 1-adrenergic receptors, provoked a significant rise of GH release. The effect was concentration dependent between 100 nM and 10 microM. The stimulatory effect of EPI and PHE was lowered, respectively blocked, by low concentrations of the potent alpha 1-adrenergic antagonist prazosin. The EPI-induced GH release could be totally blocked only by administration of both alpha- and beta-receptor antagonists. Under the same conditions and using concentrations up to 1 microM, the alpha 2-agonist clonidine had no or only a slight stimulatory effect; dopamine had no effect. Administration of both PHE and ISO resulted in a more than additive stimulation of GH release. The effectiveness of PHE but not clonidine, together with the high potency of the alpha 1-blocker prazosin suggest that the alpha-adrenergic receptor is predominantly of the alpha 1-subtype. When tested on days 1, 3, 6 and 8 in culture, both alpha- and beta-adrenergic responses appeared to be higher in the presence of the glucocorticoid dexamethasone compared to the responses in the absence of dexamethasone.(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulation and inhibition of prolactin release from rat pituitary lactotrophs by the cholinomimetic carbachol in vitro. Influence of hormonal environment and intercellular contacts.

The prolactin (PRL) response of perifused rat pituitary tissue to the cholinomimetic agent carbachol (CARB) was studied under various in vitro conditions. Perifusion of freshly removed hemipituitaries from 14-day-old rats with CARB did not affect basal PRL release. When established in organ culture for 3 days in a serum-free chemically defined medium, there was a significant increase of PRL release in response to CARB. This PRL releasing activity of CARB depended on the hormonal environment of the culture medium: supplementation of the culture medium with triiodothyronine (T3) and the glucocorticoid dexamethasone (DEX) completely reversed the PRL releasing activity of CARB into an inhibition of PRL release. In dispersed pituitary cells from immature rats, cultured as three-dimensional reaggregates, a similar reciprocal responsiveness to CARB existed which was also determined by T3 and DEX. This reciprocal responsiveness to CARB was preserved in adult female rats but was shifted to a more prominent inhibition in adult male rats. Tumoral PRL secreting GH3 cells, cultured as aggregates, always responded in an inhibitory way, irrespective of the hormonal environment. The expression of the reciprocal responses, in particular of the inhibitory pathway to CARB was dependent on close cellular contacts, as the inhibitory response of normal and tumoral pituitary cells, cultured as isolated cells on Cytodex beads, was completely absent. The stimulatory response of normal lactotrophs, cultured as isolated cells was, although attenuated, still preserved. The present data suggest that there exists a reciprocal responsiveness of normal lactotrophs to cholinomimetics depending on the hormonal environment and close cellular associations. In contrast, only inhibitory PRL responses occur in GH3 tumoral lactotrophs, which are not dependent on thyroid and glucocorticoid hormones.

Cellular distribution of lesions in Batten disease.

One of the characteristic manifestations of chronic neuronal lipofuscinosis (Batten disease) is a marked predisposition for epileptic seizures. The management of these seizures is very difficult. The present study was initiated to determine what mechanisms could account for the seizure disorder. Tissue was examined from a patient with a history of Batten disease that was histologically verified. Reduced silver and Golgi impregnations were done on the parietal cortex of the patient. There was no evidence of the marked dendritic abnormalities seen in classic epileptic foci. Instead there was marked swelling and dilatation of the axon hillock and initial segment. This finding suggested that inhibition of these pyramidal neurons was markedly attenuated due to disruption of initial segment inhibitory synapses. Studies are continuing to determine if the GABA decreases seen in Batten disease may in part be due to trophic sequences brought about by loss of these critical inhibitory synapses.

Free radicals, anticonvulsants, and the neuronal ceroid-lipofuscinoses.

The relationship between free radicals and scavenger enzymes, and the disorders called the neuronal ceroid-lipofuscinoses, has long been an argumentative one. Recent evidence would seem to support the fact that such a relationship might exist but that it is indirect. The relationship does not seem due to an inborn error of free radical scavenger enzyme metabolism. Anticonvulsants play a role, as they influence free radical generating systems. At this juncture, no one has studied the relationship of anticonvulsant therapy, neuronal ceroid-lipofuscinosis, and the free radical-scavenging enzyme system, and their interplay. We have studied a large number of patients with epilepsy who are on either monotherapeutic or polytherapeutic regimens of most of the common anticonvulsants. We have found excessive free radical production in many of these patients, ranging from minor effects in the simpler anticonvulsants when used monotherapeutically, to more complex changes in polytherapeutic combinations. Likewise, we have found subtle and inconsistent findings in the free radical-scavenging enzyme system in a variety of examples of neuronal ceroid-lipofuscinosis. When refractory seizure disorders stimulate the vigorous use of polytherapy with a variety of free radical-facilitating anticonvulsants, free radical production becomes deleterious. Likewise, in certain types of neuronal ceroid-lipofuscinosis, polypharmacy with anticonvulsants, by enhancing the production of free radicals or suppressing scavenging enzymes, tends to be deleterious and induces a worsening in the disease process.

Pontine cryptococcoma in a nonimmunocompromised individual: MRI characteristics.

The case of a pontine cryptococcoma in a nonimmunocompromised, previously healthy 16-year-old boy is presented. The patient had slowly progressive brainstem signs with right cranial nerves V, VII, and VIII palsies, and contralateral corticospinal and spinothalamic deficits. Magnetic resonance images (MRI) revealed, within the right pons, a 1-cm diameter round mass lesion, hypointense on T1-weighted images, hyperintense on T2-weighted images, and with rim enhancement after infusion of gadopentetate dimeglumine. This is the only report of the MRI findings in an isolated pontine cryptococcoma in an immunocompetent patient. Early recognition of this specific MRI pattern is essential, because complete recovery can be achieved with prompt antifungal treatment.

Imaging through the posterior fontanelle.

Sonography of the posterior fontanelle is easily performed and yields exquisite details of the outline of the major structures of the posterior fossa and the tentorium. These structures are more clearly outlined through the posterior fontanelle than via the traditional anterior fontanelle approach, probably because the longitudinal axis of the sonographic beam passing through the posterior fontanelle is nearly perpendicular to the outline of the aqueduct of Sylvius, the fourth ventricle, the brain stem, the cerebellar vermis, and the tentorium. Several cases are presented briefly to illustrate the sonographic appearance of the normal and abnormal infratentorial anatomy via a posterior fontanelle approach.

Mitochondrial encephalopathies.

Although no single neurological manifestation is specific of mitochondrial encephalopathies, several neurological syndromes are clearly suggestive of the diagnosis. Muscle biopsy for histochemicals, biochemical, and mitochondrial DNA studies is frequently necessary to establish diagnosis of mitochondrial encephalopathy presenting with such neurological syndromes. Mitochondrial encephalopathies most frequently result from nuclear gene defects and biochemical studies are frequently helpful in reaching a specific diagnosis. Various therapeutic interventions are beneficial in selected cases.

Cerebellar infarct: late complication of the Fontan procedure?

Cardiac disease is present in approximately 30% of children with stroke. Other case reports have documented stroke in patients who have previously undergone the Fontan procedure for correction of tricuspid atresia. Most of these strokes have occurred in the immediate postoperative period. There has been one report of a cerebral infarction 3 1/2 months after surgery. We report a child with superior cerebellar artery distribution infarction after undergoing the Fontan procedure 24 months previously. Previous reports of stroke in patients having undergone the Fontan procedure and possible etiologies for these strokes are discussed. We believe our patient had the longest procedure-to-stroke interim yet reported.

The use of neuropsychological evaluation in the medical management of subdural empyema.

Subdural empyema is in itself an uncommon complication of infection in childhood and localization of the infection to the parafalcine area is rare. This paper presents a case study of a teenager with subdural empyema resulting from paranasal sinusitis, who presented as a parafalcine syndrome and was treated successfully without neurosurgical intervention. Results of repeat neuropsychological evaluation (premorbid, 17 days into treatment, and after six months), correlated with changes seen on serial CT scanning during treatment and follow up. More importantly, the neuropsychological evaluation was clinically more sensitive than the traditional neurological examination in assessing changes in cortical integrity during the course of recovery. Thus, neuropsychological evaluation proved to be a valuable supplement to the neurological examination in exploring morbidity and assisting in treatment decision making in the management of subdural empyema.

Cerebellar hemorrhage: a major morbidity in extremely preterm infants.

OBJECTIVE: To determine the impact of cerebellar hemorrhage (CH) on mortality and adverse neurodevelopmental (ND) outcome rates in extremely preterm infants admitted to a tertiary neonatal unit. STUDY DESIGN: A total of 1120 eligible infants (<28 weeks gestation) were born from 1998 to 2008 and had at least one cranial ultrasound. ND outcome was determined at 12 to 18 months corrected age. RESULTS: Most CH (75%) occurred in infants <25 weeks gestation. CH did not affect mortality rates, however, it was associated with both mental and motor impairments, with incidence rate ratios of 3.08 (1.71 to 4.84) and 2.12 (1.12 to 3.45), respectively. Moreover, the risk of cerebral palsy (CP) was increased in infants with CH involving the medial part of the cerebellum. CONCLUSION: Our findings substantiate recent reports about the cerebellum, highlighting its role in cognitive and executive functions, and associating early cerebellar injury not only with CP but also with learning, affective and behavioral disorders.

Intracranial hemorrhage and cerebral angiopathic changes in a suicidal phenylpropanolamine poisoning.

A 27-year-old man had an intracerebral hemorrhage and angiographic evidence of cerebral vasculitis after suicidal ingestion of 13 nasal decongestant tablets containing phenylpropanolamine (PPA). Toxicology screen and gas chromatography demonstrated PPA in the urine. Phenylpropanolamine is found in many over-the-counter preparations, but physicians should be aware of PPA's side effects and should be cautious about prescribing this potentially hazardous drug to suicidal patients.

History of the cerebrohepatorenal syndrome of Zellweger and other peroxisomal disorders.

The history of the peroxisomal disorders (PDs), including the most frequent variant, the cerebrohepatorenal syndrome of Zellweger, can be divided into four phases. During the first phase, lasting from 1964 to 1972, the clinical and pathologic manifestations of Zellweger's syndrome (ZS) were explored and delineated. In 1973 it was found that ZS is due to the absence of peroxisomes in hepatocytes and renal tubular epithelial cells. With this discovery the second phase of ZS was initiated, which in subsequent years led to discovery of various defective peroxisomal functions. During the third phase, beginning in 1980, various other peroxisomal disorders were discovered, among them infantile Refsum's disease, hyperpipecolic acidemia, neonatal adrenoleukodystrophy, and rhizomelic chondrodysplasia punctata. During 1986 the etiology of the various PDs was identified by complementation studies, marking the beginning of the fourth phase of the history of the peroxisomopathies. It was found that ZS, neonatal adrenoleukodystrophy, and rhizomelic chondrodysplasia punctata represent different genetic entities, while Refsum's disease and hyperpipecolic acidemia are alleviated variants of ZS. Moreover, results of preliminary studies indicate that cells of one case of ZS may complement the cells of another ZS case, which could indicate genetic heterogeneity of ZS.

Maternal-fetal transport of vitamin K1 and its effects on coagulation in premature infants.

We conducted a prospective study to determine (1) the maternal-fetal vitamin K1 transport in premature infants after vitamin K1 was given to the mothers antenatally and (2) the vitamin K1 effects on blood coagulation in the babies. Women in labor at less than or equal to 34 weeks of gestation were randomly selected to receive antenatal vitamin K1, 5 mg given intramuscularly (vitamin K1 group), or no vitamin K1 (control group). Eight infants, including one set of twins, were in the vitamin K1 group and six in the control group. Vitamin K1 concentrations were higher in the vitamin K1 group than in the control group (p = 0.06). Activated partial thromboplastin time was prolonged, and factor II coagulation activity and factor II antigen were proportionately decreased in cord plasma in both groups. The average ratio of factor II coagulation activity to antigen was not decreased in either group. Protein induced by vitamin K absence-II (PIVKA-II) was not detectable in any cord plasma sample in either group. These findings support previous reports that the decreased vitamin K-dependent coagulation activity in premature infants is the result of reduced synthesis of precursor proteins, rather than the result of vitamin K deficiency, and suggest that additional vitamin K1 is not likely to improve coagulation activity. Among those infants who underwent cranial ultrasonography, all four in the vitamin K1 group and one of five in the control group had mild intraventricular hemorrhage. Studies of a larger number of patients are necessary before it can be established that maternal antenatal administration of vitamin K1 results in improvement of coagulation and the prevention of intraventricular hemorrhage in premature infants.

Glutathione peroxidase deficiency and childhood seizures.

4 children with intractable seizures, repeated infections, and intolerance to anticonvulsants had evidence of glutathione peroxidase deficiency. 2 had low intracellular enzyme activity but normal blood selenium and high plasma glutathione peroxidase concentrations. The other 2 had low intracellular glutathione peroxidase activity with low circulating glutathione peroxidase and selenium concentrations. The clinical state of the children improved after discontinuation of anticonvulsant medication and selenium substitution.

Magnetic resonance imaging of mesial temporal sclerosis: case reports.

Two patients with uncontrollable complex partial seizures had normal findings on pre- and postinfusion computed tomography scans. Magnetic resonance imaging demonstrated, in both patients, a lesion in the temporal lobe suggestive of mesial temporal sclerosis. One patient underwent temporal lobectomy, and the radiologic diagnosis was verified. In patients with complex partial seizures, magnetic resonance imaging appears to be able to noninvasively localize temporal lobe lesions in preparation for surgical intervention.

Altered antioxidant enzyme activities in children with a serious adverse experience related to valproic acid therapy.

Specific oxidative metabolites of valproic acid (VPA) have been associated with the clinically defined toxicity of the drug. To investigate the role of enzymatic detoxification in clinical toxicity, we compared activities of five antioxidant enzymes in 15 patients with a serious adverse experience (SAE) related to VPA therapy, to enzyme activities measured in 35 patients with good clinical tolerance of VPA, and 50 healthy, age-matched subjects. These enzymes included glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), glutathione transferase, superoxide dismutase, and catalase in erythrocytes; and GSH-Px in plasma. We also determined levels of Se, Cu, and Zn, trace elemental cofactors for these enzymes, in plasma from each individual. In patients with a VPA-associated SAE, GSH-Px was significantly depressed and GSSG-R was significantly elevated relative to values for the other groups. Selenium and zinc concentrations were lower in SAE patients than in controls. These findings may indicate a role for selenium dependent antioxidant activity in individual susceptibility to an SAE related to VPA therapy.