Pyridoxine-dependent epilepsy (PDE-ALDH7A1) in adulthood: A Dutch pilot study exploring clinical and patient-reported outcomes.

Background: Little is known about pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) in adulthood, as the genetic basis of the disorder has only been elucidated 15 years ago. This creates a knowledge gap for physicians, pediatric patients and their parents, which was aimed to address in this study using clinical data as well as patient-reported outcome measures (PROMs) for the patient's perspective. Methods: Dutch, genetically confirmed PDE-ALDH7A1 patients ≥18 years were eligible for inclusion. Clinical data were collected as well as PROMs (PROMIS item banks Anxiety, Depression, Anger, Physical Functioning, Cognitive Functioning, Cognitive Abilities, Ability to Participate and Satisfaction with Social Roles). Results: Ten out of 11 patients agreed to participate (91% response rate). Seizure control at last follow up (median age 25.2 years, range 17.8-29.8 years) was achieved with pyridoxine monotherapy in 70%, 20% with adjunct common-anti epileptic drugs and 10% did not obtain complete seizure control. Neurologic symptoms were present in all but one patient (90%) and included tremors, noted in 40%. Neuro-imaging abnormalities were present in 80%. Intellectual disability was present in 70%. One patient (10%) attended university, three maintained a job without assistance, five maintained a job with assistance or attended social daycare, and one patient never followed regular education. The cohort scored significantly lower on the PROMIS Cognitive Functioning compared to the general (age-related) population. Distribution of scores was wide on all PROMIS item banks. Discussion & conclusion: Outcomes of this young adult cohort are heterogeneous and individualized approaches are therefore needed. Long-term seizure control with pyridoxine was achieved for almost all patients. Neurologic symptoms were noted in the majority, including tremors, as well as neuro-imaging abnormalities and intellectual disability, additionally reflected by the PROMIS Cognitive Functioning. PDE-ALDH7A1 patients scored comparable to the general population on all other PROMs, especially regarding Ability to Participate and Satisfaction with Social Roles this may indicate a positive interpretation of their functioning. The aim is to expand this pilot study to larger populations to obtain more solid data, and to advance the use of PROMs to engage patients in research and provide the opportunity for personalized care.

Integrating neurocritical care approaches into neonatology: should all infants be treated equitably?

To improve the neurologic outcomes for infants with brain injury, neonatal providers are increasingly implementing neurocritical care approaches into clinical practice. Term infants with brain injury have been principal beneficiaries of neurologically-integrated care models to date, as evidenced by the widespread adoption of therapeutic hypothermia protocols for hypoxic-ischemic encephalopathy. Innovative therapeutic and diagnostic support for very low birth weight infants with brain injury has lagged behind. Given that concern for significant future neurodevelopmental impairment can lead to decisions to withdraw life supportive care at any gestational age, providing families with accurate prognostic information is essential for all infants. Current variable application of multidisciplinary neurocritical care approaches to infants at different gestational ages may be ethically problematic and reflect distinct perceptions of brain injury for infants born extremely premature.

Nutritional factors and anticonvulsant therapies: effect on growth in children with epilepsy.

Factors influencing growth before puberty were examined in a group of 32 epileptic children in a cross-sectional investigation. Participants in the study were divided into two groups according to what anticonvulsant drug, carbamazepine or valproic acid, they were currently taking. Dietary intakes of energy, iron, and zinc were assessed and hemoglobin and serum zinc concentrations were evaluated. Measurements of height and weight were compared with standard growth charts prepared by the National Center for Health Statistics, Hyattsville, MD. A Student's t test comparison was made along with analyses of covariance and stepwise regression, and no significant differences were found between the two groups of children in terms of height or weight. Linear growth was normal. We found that low dietary zinc intake, 64-87% of the recommended dietary allowance, was not associated with reduced height in children. In addition, neither the number of years taking anticonvulsant medication nor the total amount of drug intake had a significant effect on weight. This was an unanticipated result because valproic acid has been associated with weight gain because of increased appetite.

Longitudinal MRI findings in pyridoxine-dependent seizures.

BACKGROUND: Pyridoxine dependency is an uncommon familial cause of intractable seizures in newborns and infants. Fewer than 100 patients have been reported, and only four reports have included examples of brain imaging findings. We report the first longitudinal MRI findings in two patients with this condition. METHODS: Six brain MR scans, three each from two patients with pyridoxine-dependent seizures, were reviewed. Morphometry of selected axial images was performed to calculate the ventricle-to-brain ratio (VBR). PATIENTS: A girl, followed for 5 years, presented with intrauterine fetal seizures and neonatal seizures, and pyridoxine dependency was confirmed at 3.5 months of age. This patient had a subsequent history of poor compliance with pyridoxine therapy and severe developmental disability. A boy, followed for 9 years, presented with neonatal seizures, and pyridoxine dependency was diagnosed at 8 months of age. RESULTS: The serial MR scans demonstrated progressive dilation of the ventricular system and atrophy of the cortex and subcortical white matter together with an increase in the VBR. These progressive abnormalities were greater in the 5-year-old girl. CONCLUSION: Pyridoxine-dependent seizures are due to an inborn abnormality in the pyridoxine-dependent synthesis of gamma-aminobutyric acid (GABA). The progressive MR changes may be due to chronic excitotoxicity caused by an imbalance of cerebral levels of GABA and glutamic acid.

Glutamate decarboxylase is not genetically linked to pyridoxine-dependent seizures.

Several aspects of pyridoxine-dependent seizure (PDS) suggest a mutation affecting glutamate decarboxylase (GAD) as a possible cause. To examine the possibility of GAD linkage with PDS, the authors performed genotype analyses of three families using polymorphic markers near the GAD genes (GAD1 and GAD2). In each family, the affected siblings exhibited different genotypes for the GAD2 gene; in two families the GAD1 genotype was disparate. These findings suggest that a mutation of GAD is not directly involved in all cases of PDS.

Familial X-linked myalgia and cramps: a nonprogressive myopathy associated with a deletion in the dystrophin gene.

We report a family with an X-linked recessive disorder characterized by muscle cramps and myalgia. Nine affected male family members had high resting serum levels of creatine kinase, and well-developed musculature with calf hypertrophy but no evidence of muscular weakness. Symptoms began in childhood and did not progress. Electromyographic findings were consistent with myopathy while muscle biopsies showed nonspecific myopathic changes without evidence of storage of glycogen or lipid. Analysis of DNA revealed a deletion in the 1st third of the dystrophin gene. Western blot analysis revealed that dystrophin was smaller than that in normal samples, with no reduction in the amount of the protein present. This disorder represents a new clinical phenotype associated with a deletion in the dystrophin gene. This deletion affects a portion of the dystrophin molecule that clinically does not appear to significantly alter its function. Other patients with deletions in this region may have truncated dystrophin without clinical signs of progressive muscle disease.

Proton magnetic resonance spectroscopic imaging in childhood ataxia with diffuse central nervous system hypomyelination.

The spatial distribution of metabolite signal intensities can be measured within entire sections of the brain by proton magnetic resonance spectroscopic imaging (1H-MRSI). A group of six patients (4 unrelated girls and 2 brothers from 5 families) with childhood ataxia with diffuse CNS hypomyelination (CACH) underwent long-echo-time, single-slice 1H-MRSI. Relative to controls, there was a decrease in the signal intensity of N-acetylaspartate, choline, and creatine throughout the white matter in all six patients. We identified lactate signals in white matter in three of them with advanced disease. The degree of white matter involvement was not homogeneous over the entire patient group, but did correlate with clinical presentation. Deep and posterior white matter tended to be more involved. There were no 1H-MRSI abnormalities in the gray matter. 1H-MRSI findings suggest that this syndrome is secondary to a metabolic defect causing hypomyelination, axonal degeneration, and, in the most compromised cases, accumulation of lactate. This study shows that CACH is not limited to girls.

Multiple organ failure after ingestion of pennyroyal oil from herbal tea in two infants.

BACKGROUND: Hepatic and neurologic injury developed in two infants after ingestion of mint tea. Examination of the mint plants, from which the teas were brewed, indicated that they contained the toxic agent pennyroyal oil. METHODS: Sera from each infant were analyzed for the toxic constituents of pennyroyal oil, including pulegone and its metabolite menthofuran. RESULTS: Fulminant liver failure with cerebral edema and necrosis developed in the first infant, who died. This infant was positive only for menthofuran (10 ng/mL). In the other infant, who was positive for both pulegone (25 ng/mL) and menthofuran (41 ng/mL), hepatic dysfunction and a severe epileptic encephalopathy developed. CONCLUSION: Pennyroyal oil is a highly toxic agent that may cause both hepatic and neurologic injury if ingested. A potential source of pennyroyal oil is certain mint teas mistakenly used as home remedies to treat minor ailments and colic in infants. Physicians should consider pennyroyal oil poisoning as a possible cause of hepatic and neurologic injury in infants, particularly if the infants may have been given home-brewed mint teas.

Studies of dopamine pharmacology in molluscs.

Dopamine has been established as a putative neurotransmitter in several species of molluscs. Biochemical and neurophysiological studies of the cellular pharmacology of dopamine have revealed several properties of molluscan dopamine receptors. The biochemical synthesis and degredation of dopamine in molluscs follows the same pathways that have been described in mammals. Adenylate cyclase is present, and the receptor mediating CAMP production is blocked by neuroleptics and certain ergot alkaloids. Studies of this enzyme and of radioligand binding indicate that molluscan dopamine receptors and serotonin receptors share certain characteristics. Neurophysiological studies have shown that dopamine induces several forms of ionic conductance changes in molluscan neurons. The receptors mediating these conductance changes may be differentiated pharmacologically. Neuroleptics are antagonists at certain receptors and ergot alkaloids have been shown to be either partial agonists or antagonists. Present evidence indicates that molluscan and mammalian CNS dopamine receptors have some similarities. However, further biochemical and neurophysiological investigations will be necessary to fully characterize molluscan dopamine receptors.

Behavioral and neurochemical changes in folate-deficient mice.

Weanling mice were fed an amino acid-based diet supplemented with 0 or 11.3 mumol folic acid/kg diet for approximately 38 days to study behavior and neurochemistry in folate deficiency. After approximately 5 wk, mice fed the unsupplemented diet weighted approximately 70% as much those fed the supplemented diet. After 2 wk, mice fed the unsupplemented diet consistently discarded (spilled) more food, and after approximately 5 wk, they had spilled 3 times more than mice fed the supplemented diet. Serum folate, brain folate and brain S-adenosylmethionine of mice fed the unsupplemented diet were 4, 53, and 60% as high, respectively, as those of mice fed the supplemented diet. Pathologic changes were not evident in brain, spinal cord, or skeletal muscle of folate-deficient mice. The hypothalamic 5-hydroxyindole acetic acid/serotonin ratio and caudate dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid concentrations were lower in deficient than control mice. Folate-deficient mice develop a behavioral activity, food spilling, which may have a neurochemical basis in the serotonin and dopamine systems.

Toluene abuse embryopathy: longitudinal neurodevelopmental effects of prenatal exposure to toluene in rats.

To determine the longitudinal effects of prenatal exposure to toluene in rats, dams received daily gavage doses of toluene diluted in corn oil on Days 6 through 19 of gestation, whereas control dams received corn oil. Litters were evaluated either on Gestational Day 19, Postnatal Day 10, or Postnatal Day 21; morphometric analysis of brain and measurements of brain DNA, cholesterol, and protein were made. Prenatal toluene exposure produced growth retarded fetuses with smaller brain and caudate-putamen volumes, fewer forebrain cell nuclei (DNA), and a reduction in both hindbrain cell size (protein/DNA) and myelination per cell (cholesterol/DNA). Postnatal catch-up growth occurred in the prenatally toluene-exposed pups, and by Postnatal Day 21 these differences had resolved. However, on Postnatal Day 21, a significant reduction in forebrain myelination/cell was present in the prenatally toluene-exposed pups. Therefore, whereas the effects of toluene administered prior to the time of the brain growth spurt were, for the most part, reversible, these exposures resulted in reduced forebrain myelination that may be permanent.

Measurement of spontaneous rotational movement (circling) in normal children.

An asymmetry of basal ganglia dopaminergic function has been demonstrated in rats and related to both spontaneous and drug-induced rotation. An electronic device that measures the same kind of rotational movements in humans has been developed, and we have utilized this "rotometer" to study spontaneous rotational movement in prepubertal children. There was no significant difference between boys and girls in their average rate of rotation; however, left hemisphere-dominant boys were stronger rotators than left hemisphere-dominant girls. Both boys and girls made significantly more full turns to the left than to the right. These findings did not vary with age. Our observations are strikingly different from those obtained in previous studies of normal adults, in which women were stronger rotators than men, left hemisphere-dominant women turned to the left, and left hemisphere-dominant men rotated to the right. This study suggests that maturational changes in rotational behavior must occur, perhaps progressing to the adult pattern during puberty. The rotometer used in this study may provide useful information regarding the status of the basal ganglia in children with specific neurobehavioral conditions such as attention deficit disorder and Tourette's syndrome.

Drug-induced dystonia in neuronal ceroid-lipofuscinosis.

Neuroleptic-induced tardive dystonia is frequently refractory to therapy. We describe a 13-year-old girl with neuronal ceroid-lipofuscinosis who developed dystonia after beginning treatment with thioridazine for acute psychosis. Although anticholinergic drugs and benzodiazepines were ineffective, the patient improved with baclofen. Patients with certain degenerative diseases of the central nervous system may be at increased risk for the development of drug-induced dystonia, and we caution against the use of neuroleptics in these patients.

Brain injury and protective effects of hypothermia using triphenyltetrazolium chloride in neonatal rat.

Colorless 2,3,5-triphenyltetrazolium chloride (TTC) is reduced by enzymes in functioning mitochondria to a red-colored compound, and has been used to differentiate areas of viable tissue from areas of infarction in adult animals. TTC was used to study the central nervous system protective effects of hypothermia on the neonatal rat exposed to hypoxia and ischemia. The effect of hypothermia on survival and weight gain was also determined. Seven-day-old Wistar rats with right carotid artery ligation were exposed to 3 hours of 8% oxygen and maintained at either 37 degrees C (n = 22) or 30 degrees C (n = 18). The survivors were sacrificed 2 days later and brain slices exposed to TTC. These slices were photographed and the percentage of damage to the right brain was estimated gravimetrically from the stained and unstained areas of enlarged images. The mean weight gains were 4.2 +/- 1.2 gm in the 30 degrees C group and -1.0 +/- 2.8 gm in the 37 degrees C group (P < .001). The survival in the 37 degrees C group was 77% and in the 30 degrees C group 100% (P < .025). The mean percentage damage to the right side of the brain in the 37 degrees C group was 45.5% (range: 0-87.5%); there was no detectable damage in any of the 30 degrees C group pups (P < .0001). In our study, TTC proved to be a rapid and simple method for assessing central nervous system injury in the neonatal rat. This study also confirms that moderate hypothermia is protective against hypoxic-ischemic brain injury.

Myeloradiculopathy associated with wasp sting.

A 12-year-old girl developed a reversible myeloradiculopathy 1 week after a wasp sting. Delayed neurologic hypersensitivity reactions to Hymenopteran stings occur primarily in adults. Reactions involving both the peripheral and central nervous systems are extremely rare and have never been reported in a child. The mechanisms underlying this uncommon reaction may be related to age-dependent differences in immunologic responses.

Nemaline myopathy associated with hypertrophic cardiomyopathy.

Nemaline myopathy is not usually considered to involve cardiac muscle and rarely is associated with nocturnal hypoventilation. We report a boy, 5 1/2 years of age, with nemaline myopathy who presented with respiratory failure. Echocardiography demonstrated the septum to left ventricular posterior wall ratio to be increased which is consistent with a hypertrophic cardiomyopathy. Because of nocturnal hypoventilation, tracheostomy was placed for ventilatory assistance. A process involving both muscle and nervous tissue may underlie this congenital myopathy; routine cardiac and pulmonary function evaluations may be indicated in these patients.

Life-threatening congestive heart failure as the presentation of centronuclear myopathy.

Myocardiopathy is associated infrequently with centronuclear myopathy. We present biopsy studies of a 15 1/2-year-old black male who presented with profound acute congestive heart failure and diffuse muscular atrophy. Cardiac symptoms had been present for 6 months; limb weakness had been unassociated with either infantile hypotonia or developmental delay. Cardiac catheterization demonstrated a dilated myocardiopathy and poor left ventricular contractility. Biopsies of both ventricles revealed striking hydropic degeneration and fibrosis. Right triceps biopsy disclosed centronuclear myopathy. Because the spectrum of disease expression in centronuclear myopathy is extensive, an association with cardiac disease always should be considered in these patients. In addition, we recommend that patients who present with idiopathic myocardiopathy should be evaluated for this and other skeletal muscle diseases.

Stable-isotope dilution GC-MS for determination of toluene in submilliliter volumes of whole blood.

An accurate and sensitive yet simple protocol for the analysis of toluene in submilliliter quantities of whole blood using stable-isotope dilution GC-MS has been developed and evaluated for use in pharmacokinetic studies of toluene exposure. The method involves the use of toluene-d8, a relatively inexpensive chemical used as a solvent for nuclear magnetic resonance spectroscopy, as an internal standard and extraction with pentane. This procedure allows for the determination of toluene in whole blood down to approximately 5 ng/mL and is suitable for pharmacokinetic measurements and biomonitoring of exposure to toluene.