Repeat instability in the 27-39 CAG range of the HD gene in the Venezuelan kindreds: Counseling implications.

The instability of the CAG repeat size of the HD gene when transmitted intergenerationally has critical implications for genetic counseling practices. In particular, CAG repeats between 27 and 35 have been the subject of debate based on small samples. To address this issue, we analyzed allelic instability in the Venezuelan HD kindreds, the largest and most informative families ascertained for HD. We identified 647 transmissions. Our results indicate that repeats in the 27-35 CAG range are highly stable. Out of 69 transmitted alleles in this range, none expand into any penetrant ranges. Contrastingly, 14% of alleles transmitted from the incompletely penetrant range (36-39 CAGs) expand into the completely penetrant range, characterized by alleles with 40 or more CAG repeats. At least 12 of the 534 transmissions from the completely penetrant range contract into the incompletely penetrant range of 36-39 CAG repeats. In these kindreds, none of the individuals with 27-39 CAGs were symptomatic, even though they ranged in age from 11 to 82 years. We expect these findings to be helpful in updating genetic counseling practices.

Pediatric patients with undetectable anticonvulsant blood levels: comparison with compliant patients.

Undetectable anticonvulsant blood levels indicate sustained noncompliance (several consecutive doses missed). We compared 91 consecutive outpatients with epilepsy and undetectable anticonvulsant blood levels to 100 patients seen during the same time period, verified as compliant by acceptable serum levels. We hypothesized that pay status, application for Supplemental Security Income, patient age, history of missed appointments, and functional status would differ between compliant and noncompliant patients. We were surprised to find large differences between clinic and insurance patients and between Caucasian and non-Caucasian patients. The 100 compliant patients included 44 Caucasian and 56 non-Caucasian patients, whereas only 9 of 91 noncompliant patients were Caucasian, and only 9 had insurance, compared to 32 compliant patients. Applications for Supplemental Security Income and history of missed appointments were significantly associated with noncompliance, but patient age, seizure type, and seizure control were not. Uninsured Caucasians were more often compliant than non-Caucasians were. Many noncompliant patients had mild epilepsy, which was reportedly doing well. Race and pay status were closely correlated. Several noncompliant females became pregnant, whereas no compliant patients did. Compliant patients were much more likely to be accompanied by a parent or caretaker on clinic visits than noncompliant patients. Noncompliant patients had at least one acceptable subsequent serum level, although 2 patients with intractable epilepsy had undetectable serum levels on three or more occasions. Noncompliance may respond to discussion and advice. We reviewed 124 episodes of undetectable drug levels in the 91 noncompliant patients. Eighteen of these resulted in hospitalization, but in 25 cases, we were told that there had been no seizures since the preceding visit. Many noncompliant patients have infrequent seizures, even if they take little or no medication. Socioeconomic status influences health, life expectancy, and educational success, but it has been claimed to be irrelevant to compliance and adherence issues in epilepsy. Our data and the experience of other centers with childhood diabetes suggest that socioeconomic, racial, and family factors influence compliance or adherence to treatment for many chronic conditions. Educational efforts and support for parents at the start of anticonvulsant treatment may improve compliance. Uninsured patients missed more appointments and were much more likely to be noncompliant than insured patients. Attention to the special problems of Medicaid and minority children is needed.

Anticonvulsant blood levels: historical review with a pediatric focus.

Epilepsy is heterogeneous and its treatment is often complicated by variable drug responses. Buchtal et al reported a close correlation between serum phenytoin levels, electroencephalographic findings, and clinical status in 1960. They suggested that physicians adjust dosage to attain a "therapeutic level." The concept was enthusiastically received. "Therapeutic serum levels" were proposed for most anticonvulsant drugs, and by 1975, most authorities believed that pharmacokinetic factors explained individual differences in drug response. However, Froscher found that measuring levels did not improve patient outcome. More recently, Schumacher's double-blind study found no correlation between phenytoin levels and seizure control or adverse effects. Pharmacodynamic variables (differences in drug responsiveness) are more important than pharmacokinetic factors for many drugs, especially receptor-active drugs. Pharmacokinetic variables were studied first, and led to a simplistic model. They are less significant than pharmacodynamic factors in the case of warfarin anticoagulation. Anticonvulsant levels can reveal noncompliance and pharmacokinetic differences. They say nothing about pharmacodynamics. Reports of "subtherapeutic levels" imply a need to increase dosage, but this is not supported by outcome data. We still lack evidence that specific drug levels are a valid intermediate target 40 years after Buchtal's paper. Responses to some anticonvulsants could depend primarily on pharmacokinetic factors, while pharmacodynamic factors could be supreme for others.

Ambulatory management of children with epilepsy.

Pediatricians can satisfactorily manage epilepsy in children if the diagnosis is confident and if continuity of care and compliance are obtained. The health hazards of epilepsy are overstated, and good outcomes can be expected for most children. If the child has definite motor seizures with an obvious neurologic handicap, parents should be given the option of AED treatment. This type of patient is more likely to develop chronic, refractory epilepsy. If the child is neurologically normal or the diagnosis is uncertain, it is better not to begin therapy after the initial seizure. Simple precautions can reduce the likelihood of injury from seizures, regardless of whether an AED is prescribed. The child and the family are the focus of treatment, not the seizures. There is much more to treating diabetes than prescribing insulin, and much more to the management of epilepsy than prescribing AEDs.

Cocaine babies: a result of multiple teratogenic influences.

The history of cocaine use is reviewed. Cocaine teratogenesis has only recently been studied, and initial human studies had serious methodological flaws. These flaws included ascertainment bias, publication bias (studies finding cocaine effects have been more likely to be presented or published), and overemphasis on the perinatal period. Comparison with alcohol teratogenesis shows that alcohol is a more potent teratogen, which, however, produces major and specific effects (fetal alcohol syndrome) in less than 10% of offspring with heavy alcohol exposure during pregnancy. Nonspecific minor congenital anomalies or fetal alcohol effects are seen in a larger number. Personal experience with two groups of children exposed to cocaine in utero is reviewed. Insurance patients gained weight, took vitamins, and generally, their children did well in spite of cocaine use. Indigent patients were usually unmarried and often "street people," probably used more cocaine, generally used other drugs as well, often did not gain weight during pregnancy, and were much more likely to have children with problems. Surveys show that most cocaine users also use alcohol, often simultaneously. Those who use both agents are more likely to have troubled backgrounds and antisocial behavior and to drop out of treatment programs than those who use only alcohol. Cocaethylene or ethylbenzoylecgonine is formed in the liver when cocaine and alcohol are simultaneously ingested. It is a potent stimulant and dopamine uptake blocker that is more toxic to myocardial cells than is cocaine. Good nutrition is now known to be very important in preventing congenital anomalies and fetal death. A multihit model of neurologic handicap, which stresses the importance of a good postnatal environment, is briefly outlined.(ABSTRACT TRUNCATED AT 250 WORDS)

Vitamin neurotoxicity.

Vitamins contain reactive functional groups necessary to their established roles as coenzymes and reducing agents. Their reactive potential may produce injury if vitamin concentration, distribution, or metabolism is altered. However, identification of vitamin toxicity has been difficult. The only well-established human vitamin neurotoxic effects are those due to hypervitaminosis A (pseudotumor cerebri) and pyridoxine (sensory neuropathy). In each case, the neurological effects of vitamin deficiency and vitamin excess are similar. Closely related to the neurological symptoms of hypervitaminosis A are symptoms including headache, pseudotumor cerebri, and embryotoxic effects reported in patients given vitamin A analogs or retinoids. Most tissues contain retinoic acid (RA) and vitamin D receptors, members of a steroid receptor superfamily known to regulate development and gene expression. Vitamin D3 effects on central nervous system (CNS) gene expression are predictable, in addition to the indirect effects owing to its influence on calcium and phosphorus homeostasis. Folates and thiamine cause seizures and excitation when administered in high dosage directly into the brain or cerebrospinal fluid (CSF) of experimental animals but have rarely been reported to cause human neurotoxicity, although fatal reactions to i.v. thiamine are well known. Ascorbic acid influences CNS function after peripheral administration and influences brain cell differentiation and 2-deoxyglucose accumulation by cultured glial cells. Biotin influences gene expression in animals that are not vitamin-deficient and alters astrocyte glucose utilization. The multiple enzymes and binding proteins involved in regeneration of retinal vitamin A illustrate the complexity of vitamin processing in the body. Vitamin A toxicity is also a good general model of vitamin neurotoxicity, because it shows the importance of the ratio of vitamin and vitamin-binding proteins in producing vitamin toxicity and of CNS permeability barriers. Because vitamin A and analogs enter the CNS better than most vitamins, and because retinoids have many effects on enzyme activity and gene expression, Vitamin A neurotoxicity is more likely than that of most, perhaps all other vitamins. Megadose vitamin therapy may cause injury that is confused with disease symptoms. High vitamin intake is more hazardous to peripheral organs than to the nervous system, because CNS vitamin entry is restricted. Vitamin administration into the brain or CSF, recommended in certain disease states, is hazardous and best avoided. The lack of controlled trials prevents us from defining the lowest human neurotoxic dose of any vitamin. Large differences in individual susceptibility to vitamin neurotoxicity probably exist, and ordinary vitamin doses may harm occasional patients with genetic disorders.(ABSTRACT TRUNCATED AT 400 WORDS)

GABA and epilepsy: their complex relationship and the evolution of our understanding.

Because of its abundance in the brain, its ability to produce hyperpolarizing inhibition of almost all neurons, its association with benzodiazepines, and the discovery that many convulsants inhibited its synthesis, gamma-aminobutyric acid (GABA) has often appeared to be the key to epilepsy. Many assumed that "primary" or "genetic" epilepsy must be a disorder of GABA synapses and that GABA agonists would be universal anticonvulsants if permeability and drug metabolism were controlled. The GABA synthetic gene was a logical "candidate gene" for epilepsy. However, the GABA-deficiency theory of epilepsy is less convincing today. GABA agonists were found to intensify seizures in some rodent and human cases. Absence and other generalized seizures in humans often worsened when treated with GABA transaminase inhibitors such as gamma-vinyl-GABA. Surprisingly, the GABA transaminase inhibitors appear to be more useful in partial than in generalized epilepsies. Neuronal GABA uptake blockers are proconvulsant. GABA agonists aggravate seizures in several mutants, ranging from the photosensitive baboon to the genetically epilepsy-prone rat. How can this be understood? Muscimol injections into the pedunculopontine nucleus increase seizures due to systematically administered convulsants, while the receptor blocker bicuculline suppresses seizures after injection into several brain regions, including the striatum. The result of inhibiting inhibitory circuits is excitation. Studies with GABA uptake blockers and the GABAB agonist baclofen are presented in which their combined administration provoked seizures in rats. Baclofen was shown also to increase the incidence of seizures evoked by pentylenetetrazole without increasing seizures due to local injections of excitatory amino acids. Baclofen antagonized the myoclonic effect of 5-hydroxytryptophan in rats with serotonin lesions. Baclofen augments some seizures and inhibits others. Selective inhibition of a particular tract, whether GABAergic or not, may have convulsant or anticonvulsant effects, depending on its connections and the state of the organism. GABAA receptor stimulation is usually but not always anticonvulsant. GABAB receptor stimulation may facilitate absence seizures and related primary generalized seizures. GABAB receptors may be abnormal in some forms of nonfocal epilepsy seen in childhood. It is likely that mutations of GABA transporter and GABAA receptor genes will be found in humans but they will probably not be patients with "pure epilepsy."

Tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM): treatment with an anabolic steroid danazol.

Tropical spastic paraparesis or HTLV-I-associated myelopathy is a progressive spastic disorder associated with the human T-lymphotropic virus type I. Some cases have responded to prednisone. Danazol is an attenuated androgen with minimal virilizing effects. It is used in the treatment of endometriosis and various autoimmune hematologic diseases shown to be responsive to prednisone. Because danazol is anabolic, useful in prednisone-responsive diseases, and less toxic than prednisone, we gave danazol to 6 patients with TSP and 1 with HIV, HTLV-I-associated myelopathy. Five patients had a favorable response. Two became ambulatory after having been confined to a wheelchair. Three were able to ambulate greater distances (in walkers) than prior to danazol. Three had noticeable decreases in spasticity. Urinary incontinence resolved in two. Physical therapy was variably employed in all except one patient. Two patients who had not responded to physical therapy responded to physical therapy and danazol. One patient did not tolerate danazol and one patient did not improve. Toxicities noted were mild elevations in liver enzymes in 4 patients; these responded to a decrease in dose of danazol; amenorrhea in one and mild fluid retention in one. We conclude that danazol is a useful agent in the management of TSP.

Folate interactions with cerebral G proteins.

Intracerebral folate injections produce convulsions and brain lesions, folic acid itself and tetrahydrofolate being more potent toxins than 5-methyltetrahydrofolate, the primary folate of mammalian extracellular fluids. Folates are known to excite neurons, by unknown mechanisms Folates stimulate GTP binding and GTPase activity in slime molds. We observed folate stimulation of GTP gamma S binding and inhibition of high affinity GTPase activity in rat brain membranes. Three fold stimulation of GTP gamma S binding was observed in cerebellar membranes treated with 50 microM FA. Folic acid (FA), dihydrofolate (DHF) and tetrahydrofolate (THF) were much more potent than 5-methyltetrahydrofolate in this regard. The effect varies between brain regions and was greatest in cerebellar and hippocampal membranes. Folates inhibit GTPase activity, with DHF and FA being the most potent and maximum inhibition being to 33% of control values. We find high affinity guanine nucleotide sensitive binding of [3H]FA in cerebellar membranes, another response typical of G protein coupled membrane receptors. Folates were also shown to stimulate the release of [3H]GDP from brain membranes. These effects are seen in washed brain membranes and can not be explained by any known folate metabolic or coenzyme functions. They resemble the effects of cholera toxin, except for their reversibility. They may be relevant to known folate neuroexcitant effects of folates.

Myoclonus: analysis of monoamine, GABA, and other systems.

Myoclonus is a clinical term meaning a quick involuntary jerk, seen in normal subjects under certain circumstances, including sleep, and in certain disease states. It is important as a symptom that may impair function and as an indicator of neurological dysfunction. Not until patients with myoclonus and major functional disability were reported in the 1960s was attention given to understanding its basis and pharmacotherapy. Reports of myoclonus developing after anoxic brain injury, and its response to treatment with the serotonin precursor 5-hydroxytryptophan (5-HTP), drew special attention. Further experience showed that only a few patients with myoclonus benefit from 5-HTP therapy. Benzodiazepines (BDZs) are often helpful in the treatment of myoclonus. Their beneficial effects decline with chronic administration because of drug tolerance, and the theoretical basis for BDZ responses remains unclear. The relationships between myoclonus, clonus, and epilepsy are discussed, as is the possible contribution of slow signaling transmembrane receptors to synchronization of motoneuron firing, which is suggested as a hallmark of myoclonus. Myoclonus may originate in many CNS sites, but the brain-stem reticular formation is especially relevant to myoclonus. Brain-stem serotonin neurons have special influence on spinal motoneurons, on startle responses, and on myoclonus. Among 5-HT receptors, 5-HT1A receptors are related to some forms of myoclonus, although 5-HT2 receptors are also implicated. GABAA receptors are related to some forms of myoclonus. Blockade of GABAA receptors or GABA synthesis regularly evokes convulsive seizures, but administration of many GABA agonists and some GABA uptake blockers paradoxically may evoke myoclonus. Injection of GABA receptor blockers into some brain areas has anticonvulsant effects. Stimulation of GABAA receptors may therefore promote or antagonize myoclonus depending on which GABA receptors are involved, the state of the system, etc. The role of glycine receptors is well established in some animal models, but has yet to be clearly established for human myoclonus. Opiates may produce myoclonus when given intrathecally or in high dosage. The concept of excitant anesthetics and special function of certain GABA receptors is discussed.

Opsoclonus-ataxia due to childhood neural crest tumors: a chronic neurologic syndrome.

Five children with subacute or acute onset of cerebellar ataxia and opsoclonus are described. Two had cerebrospinal fluid pleocytosis at the onset of ataxia and were initially thought to have acute parainfectious cerebellar ataxia of childhood. All were found to have tumors of neural crest origin (two neuroblastomas, three ganglioneuroblastomas). Tumors were small and only found by computed tomographic techniques. Urinary catecholamine metabolites were elevated in only two of the patients. Four of the five failed to improve neurologically with resection of the tumor. All four have had a steroid-sensitive chronic ataxic syndrome that worsens with acute nonspecific illnesses and has resulted in long-term deficits, particularly in speech and gross motor function. This is a metabolic encephalopathy associated with permanent residual neurologic deficits but without visible lesions on neuroimaging studies. We stress the frequency of cerebrospinal fluid pleocytosis in patients with tumor-associated opsoclonus and the clinical difficulty in separating tumor-associated cases from those due to other causes [corrected].

Huntington's disease in Venezuela: 7 years of follow-up on symptomatic and asymptomatic individuals.

Persons symptomatic and at risk for Huntington's disease (HD) from a large extended family in the state of Zulia, Venezuela, have been followed prospectively for 7 years. Between 1981 and 1988, 593 people were examined, of whom 128 had symptomatic HD and 171 persons at risk had examination abnormalities that were insufficient to meet criteria for diagnosis. The remaining 294 had normal examinations. Abnormalities of saccadic eye movement and slowness of rapid alternating movements were the most common abnormalities found in at-risk individuals. Thirty persons who did not meet criteria for diagnosis at their first examination have subsequently been diagnosed with symptomatic HD. Their average age at diagnosis was 33.5 +/- 8.3 (SD) years. The likelihood of developing symptomatic HD within 3 years was 3% for those persons with normal first examinations, 23% for those with mildly abnormal first examinations, and 60% for those with highly abnormal first examinations. The rate of disease progression in early symptomatic cases were 1.4 +/- 0.1 (SEM) points per year on the Shoulson-Fahn functional capacity scale. Paternal or maternal inheritance did not appear to affect the rate of progression in this group of individuals. The data suggest that there is not a discrete age of onset but rather a prolonged period of time during which symptoms unfold.

The role of mitochondrial DNA in Huntington's disease.

Huntington's disease is generally considered to be a late-onset neurodegenerative disorder, which follows a protracted course of deteriorating motor control and cognitive impairment. However, in a minority of cases, the onset of symptoms occurs early in life. A preponderance of the juvenile-onset HD victims have inherited the genetic defect from their fathers. This variation in age of onset, based on the sex of the affected parent, has suggested that maternally inherited genes may influence expression of the disorder. We describe a portion of a large Venezuelan HD pedigree in which both the mother and father of three juvenile-onset HD patients share a common maternal lineage. Scanning of mtDNA from members of this family with 43 restriction endonucleases failed to reveal any differences in the mitochondrial genotype that could account for the difference in age of onset between the affected father and his progeny. Members of a related family with an affected father but no juvenile-onset progeny also appeared to share the same mitochondrial genotype. In addition, the mitochondrial gene products from lymphoblast cell lines of these family members were analyzed on polyacrylamide gels after incubation of cells with [35S]methionine, but no detectable alterations were seen. Taken together, these data suggest that the maternally inherited mitochondrial genome does not play a crucial role in determining in age of onset in HD.

Very-high-dose phenobarbital for refractory status epilepticus in children.

Status epilepticus refractory to initial anticonvulsant therapy is a serious condition with a high morbidity and mortality. We present 50 cases with refractory status epilepticus (RSE) treated with very-high-dose phenobarbital (VHDPB) without reference to a predetermined maximum level or dose. Maximum serum levels ranged from 70 to 344 micrograms/ml (median, 114 micrograms/ml). VHDPB controlled seizures in all cases where no limits were imposed upon maximum dose (47/50). We found no maximum dose beyond which further doses are likely to be ineffective. Forty patients were intubated prior to VHDPB, but recovered respiratory drive and could be removed from the ventilator despite very high serum levels. This is explained by acute drug tolerance. Hypotension was unusual, related to the highest levels, and easily controlled. VHDPB has many relative advantages over other therapies presently used for RSE.

The measurement of gamma-glutamyl hydrolase (conjugase) activity in rat brain.

An assay using the artificial substrate, 2,4-diamino-10-methyl-pteroylglutamyl-gamma-glutamate (MTX-G1), was developed to measure gamma-glutamyl hydrolase (conjugase), which hydrolyzes folylpolyglutamates. This assay allows us to: 1) measure conjugase for the first time in rat brain and 2) measure conjugase in a reliable, sensitive and inexpensive manner. The MTX-binding assay results were compared to samples analyzed by HPLC and found to vary by only 13%. The artificial substrate, MTX-G1, had a lower rate of hydrolysis than pteroylglutamyl-gamma-glutamate (Pte-G2), 70.7 +/- 0.64 and 92.6 +/- 0.22 nmoles/hr/mg protein respectively. Conjugase was semi-purified 24 fold in H2O and found to have a pH optimum of 5.0.

The guinea pig myoclonic model: behavioral supersensitivity to 5-hydroxytryptophan induced by intracisternal 5,7-dihydroxytryptamine.

To study the species difference of guinea pigs and rats in response to 5-hydroxytryptophan (5-HTP), we injected both animals intracisternally with 5,7-dihydroxytryptamine. In rats with 5,7-dihydroxytryptamine lesions, 5-HTP evoked the well described myoclonic-serotonergic syndrome. In the guinea pig, 5,7-dihydroxytryptamine lesions significantly increased the severity of myoclonic response to 5-HTP (150 mg/kg) compared to vehicle controls, resulting in lethal convulsions. Guinea pigs treated with 5,7-dihydroxytryptamine did not develop spontaneous myoclonus, or when treated with 5-HTP, other 'serotonergic behaviors' such as lateral head weaving, hindlimb abduction, and forepaw tapping. Guinea pigs tolerated intracisternal 5,7-dihydroxytryptamine less well than rats, with a higher mortality, although immediate post-injection convulsions were less severe and did not require phenobarbital prophylaxis. Staged lower doses of 5,7-dihydroxytryptamine (100-200 micrograms) were better tolerated than a single high dose of neurotoxin (400 micrograms). The regional profile of 5,7-dihydroxytryptamine lesions in the guinea pig resembled that of the rat, with maximal depletion of 5-HT in spinal cord and selected forebrain structures, and little effect in diencephalon and midbrain. Depletions in the guinea pig were less selective for 5-HT using desipramine pretreatment than in the rat. In naive guinea pigs and rats, regional content of 5-HT was similar. These data suggest that the functional integrity of serotonergic neurons is not requisite for the expression of myoclonus induced by 5-HTP in the guinea pig. 5,7-Dihydroxytryptamine lesions in the guinea pig resulted in behavioral and neurochemical similarities and differences in comparison with the rat.