Wang-Tso Lee

Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency

Objective: To describe the current treatment; clinical, biochemical, and molecular findings; and clinical follow-up of patients with aromatic l-amino acid decarboxylase (AADC) deficiency. Method: Clinical and biochemical data of 78 patients with AADC deficiency were tabulated in a database of pediatric neurotransmitter disorders (JAKE). A total of 46 patients have been previously reported; 32 patients are described for the first time. Results: In 96% of AADC-deficient patients, symptoms (hypotonia 95%, oculogyric crises 86%, and developmental retardation 63%) became clinically evident during infancy or childhood. Laboratory diagnosis is based on typical CSF markers (low homovanillic acid, 5-hydroxyindoleacidic acid, and 3-methoxy-4-hydroxyphenolglycole, and elevated 3-O-methyl-l-dopa, l-dopa, and 5-hydroxytryptophan), absent plasma AADC activity, or elevated urinary vanillactic acid. A total of 24 mutations in the DDC gene were detected in 49 patients (8 reported for the first time: p.L38P, p.Y79C, p.A110Q, p.G123R, p.I42fs, c.876G>A, p.R412W, p.I433fs) with IVS6+ 4A>T being the most common one (allele frequency 45%). Conclusion: Based on clinical symptoms, CSF neurotransmitters profile is highly indicative for the diagnosis of aromatic l-amino acid decarboxylase deficiency. Treatment options are limited, in many cases not beneficial, and prognosis is uncertain. Only 15 patients with a relatively mild form clearly improved on a combined therapy with pyridoxine (B6)/pyridoxal phosphate, dopamine agonists, and monoamine oxidase B inhibitors.

Neuroprotective effect of lamotrigine and MK-801 on rat brain lesions induced by 3-nitropropionic acid : Evaluation by magnetic resonance imaging and in vivo proton magnetic resonance spectroscopy

Magnetic resonance imaging and in vivo proton magnetic resonance spectroscopy were used to evaluate the therapeutic effect of lamotrigine and MK-801 on rat brain lesions induced by 3-nitropropionic acid. Systemic administration of 3-nitropropionic acid (15 mg/kg per day) to two-month-old Sprague-Dawley rats (n = 10 for each group) for five consecutive days induced selective striatal and hippocampal lesions and specific behavioral change. Pretreatment with lamotrigine (10 mg/kg or 20 mg/kg per day) or MK-801 (2 mg/kg per day) attenuated the lesions and behavioral change. There were no significant differences in T2 values of the striatum and hippocampus among rats pretreated with MK-801, lamotrigine (20 mg/kg) and sham controls. Significant elevations of succinate/creatine and lactate/creatine ratios and decreases of N-acetylaspartate/creatine and choline/creatine ratios were observed after 3-nitropropionic acid injections (P < 0.001). The changes were nearly prevented after pretreatment with lamotrigine (20 mg/kg). However, the N-acetylaspartate/creatine in rats pretreated with lamotrigine (10 mg/kg) (P < 0.01) and MK-801 (P < 0.05) still showed significant reduction as compared with sham controls. Thus we conclude that both lamotrigine and MK-801 are effective in attenuation of brain lesions induced by 3-nitropropionic acid. A higher dose of lamotrigine provides a better neuroprotective effect than MK-801. With a better therapeutic effect and fewer side effects, lamotrigine is more promising for potential clinical application.

Tumor necrosis factor α increases neuronal vulnerability to excitotoxic necrosis by inducing expression of the AMPA-glutamate receptor subunit GluR1 via an acid sphingomyelinase-and NF-κB-dependent mechanism

Abstract Acid sphingomyelinase (ASMase) and NF-κB participate in tumor necrosis factor α (TNFα) signal transduction. Mice in which the genes encoding ASMase or the p50 subunit of NF-κB are disrupted have been reported to be less vulnerable than wild-type mice to focal brain ischemia. We now demonstrate selective diminution in expression of GluR1, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-type glutamate receptor (AMPA-GluR) protein subunit, in these two groups of knockout mice. To confirm that neuronal GluR1 expression is regulated by ASMase and NF-κB, and to learn whether this regulation has pathophysiological significance, we treated cultured human NT2-N neurons with TNFα. This induced GluR1 expression and increased susceptibility of the neurons to kainate necrosis. Both induction of GluR1 and heightened vulnerability to kainate were blocked by inhibiting ASMase or by antisense knockdown of NF-κB p50. We conclude that TNFα can sensitize neurons to excitotoxic necrosis by inducing expression of GluR1 via an ASMase- and NF-κB-dependent mechanism. TNFα levels are frequently elevated during ischemia and other CNS diseases in which excitotoxicity contributes to neuronal loss. Our results suggest that inhibiting TNFα signal transduction will diminish neuronal necrosis in these diseases.

Congenital intracranial teratoma

Congenital intracranial teratoma is a rare disease. A fetus with a congenital intracranial teratoma presenting with a disproportionately enlarged head at 27 weeks gestation is presented. Prenatal ultrasonography and fetal magnetic resonance imaging demonstrate a huge, heterogenous intracranial mass in the left supratentorial region, with the left cerebral hemisphere being compressed and flattened. The infant died of respiratory failure within 24 hours of birth at 28 weeks gestation. On postmortem examination the histologic report revealed an immature teratoma. Fetal MRI is helpful in the prenatal diagnosis and evaluation of intracranial tumor.

The mechanisms of neuronal death produced by mitochondrial toxin 3-nitropropionic acid: the roles of N-methyl-D-aspartate glutamate receptors and mitochondrial calcium overload

Previous studies showed that 3-nitropropionic acid, an irreversible inhibitor of succinate dehydrogenase, produced neuronal death secondary to perturbed intracellular calcium homeostasis. However, the response of intramitochondrial calcium ([Ca(2+)](m)) to 3-nitropropionic acid remains unknown. In this study, we investigated the roles of and relationships among [Ca(2+)](m) overload, mitochondrial reactive oxygen species, and mitochondrial membrane depolarization in 3-nitropropionic acid-induced neuronal death. Following 1 mM 3-nitropropionic acid treatment on primary rat neuronal cultures, there was a gradual increase of [Ca(2+)](m) beginning at 2-4 h post 3-nitropropionic acid application, and a twofold increase of mitochondrial reactive oxygen species at 4 h. These were followed by mitochondrial membrane depolarization at 6-8 h post-treatment. By inhibiting [Ca(2+)](m) uptake, Ruthenium Red attenuated the production of reactive oxygen species, and prevented the 3-nitropropionic acid-induced mitochondrial membrane depolarization and 70% of apoptotic neuronal death (P<0.001). Inhibition of caspase activation attenuated the elevation of [Ca(2+)](m) (P<0.001), indicating that caspase activation plays a role in the elevation of [Ca(2+)](m). MK-801, an antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors, prevented 3-nitropropionic acid-induced [Ca(2+)](m) elevation, caspase-3 activation, mitochondrial depolarization, and neuronal death. We conclude that the activation of NMDA glutamate receptor contributes to mitochondrial alterations induced by 3-nitropropionic acid. Inhibition of its activation and [Ca(2+)](m) overload with subsequent mitochondrial membrane depolarization can therefore attenuate the neuronal death induced by 3-nitropropionic acid.

Molecular and clinical analyses of 84 patients with tuberous sclerosis complex

BackgroundTuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the development of multiple hamartomas in many internal organs. Mutations in either one of 2 genes, TSC1 and TSC2, have been attributed to the development of TSC. More than two-thirds of TSC patients are sporadic cases, and a wide variety of mutations in the coding region of the TSC1 and TSC2 genes have been reported.MethodsMutational analysis of TSC1 and TSC2 genes was performed in 84 Taiwanese TSC families using denaturing high-performance liquid chromatography (DHPLC) and direct sequencing.ResultsMutations were identified in a total of 64 (76 %) cases, including 9 TSC1 mutations (7 sporadic and 2 familial cases) and 55 TSC2 mutations (47 sporadic and 8 familial cases). Thirty-one of the 64 mutations found have not been described previously. The phenotype association is consistent with findings from other large studies, showing that disease resulting from mutations to TSC1 is less severe than disease due to TSC2 mutation.ConclusionThis study provides a representative picture of the distribution of mutations of the TSC1 and TSC2 genes in clinically ascertained TSC cases in the Taiwanese population. Although nearly half of the mutations identified were novel, the kinds and distribution of mutation were not different in this population compared to that seen in larger European and American studies.

Concurrent Validity of the Comprehensive Developmental Inventory for Infants and Toddlers with the Bayley Scales of Infant Development-II in Preterm Infants

BACKGROUND AND PURPOSE The Comprehensive Developmental Inventory for Infants and Toddlers (CDIIT) is a new developmental test designed in Taiwan and lacks concurrent validity information. This study investigated the concurrent validity of the CDIIT with the Bayley Scales of Infant Development-II (BSID-II) in preterm infants aged 6-18 and 21-40 months, respectively. METHODS We recruited 160 preterm infants (84 boys, 76 girls) with a corrected age of 6-18 months and followed them up until 21-40 months of age. One tester administered the CDIIT and BSID-II to all infants. Developmental ages (DAs) and developmental quotients (DQs) from both tests were analyzed with Pearson correlation and kappa tests. RESULTS Correlation coefficients for DAs and DQs between the 2 cognitive and motor subtests and classification agreements were high at 6-18 months (r = 0.80-0.97; kappa = 0.80, 0.85) and moderate to high at 21-40 months (r = 0.60-0.77; kappa = 0.44, 0.57). DQ classification for the CDIIT motor subtests tended to be higher than for the BSID-II motor scales at 21-40 months. CONCLUSIONS In preterm infants, concurrent validity between the motor and cognitive subtests of the CDIIT and the BSID-II was acceptable. The CDIIT can be thus used in clinics for the early identification of developmental delay in infants and toddlers.

Poor outcome for neonatal-type nonketotic hyperglycinemia treated with high-dose sodium benzoate and dextromethorphan.

Neonatal-type nonketotic hyperglycinemia treatment remains unsatisfactory, even if started early. A review of six patients who underwent treatment for neonatal-type nonketotic hyperglycinemia in our hospital is presented. All patients were treated with a standardized protocol. Medical histories were retrieved from case notes. All six patients had elevated cerebrospinal fluid plasma glycine levels initially. All but one had received sodium benzoate and dextromethorphan from 1 month of age. All suffered from intractable seizures and severe mental retardation, and only two patients remain alive. One patient died at 5 days of age. No resuscitation was attempted in accordance with the familys wish after genetic counseling. The prognosis of neonatal nonketotic hyperglycinemia remains poor with current treatment. Genetic counseling helps parents cope with this devastating genetic disease. (J Child Neurol 2004;19:39—42).

Levetiracetam in Continuous Spike Waves During Slow-Wave Sleep Syndrome

We investigated the clinical characteristics of children with continuous spike waves during slow-wave sleep syndrome and their treatment response to levetiracetam. Five boys and one girl, diagnosed with epilepsy with continuous spike waves during slow-wave sleep syndrome, were enrolled. Their clinical characteristics, including neuroimaging findings, were reviewed. The signs related to continuous spike waves during slow-wave sleep included increased seizure frequency (6/6), impaired responsiveness (3/6), and psychomotor regression (2/6). Magnetic resonance imaging disclosed lissencephaly in one patient, and porencephaly of the left hemisphere in another. The number of antiepileptic drugs before the use of levetiracetam was 0-4 (mean +/- SD, 2.3 +/- 1.5). Five of 6 children demonstrated a good response to levetiracetam, whereas 2 (40%) underwent a relapse of electrical status epilepticus during sleep pattern on electroencephalograms 4 and 5 months after clinical improvement. Both were 5 years old. The most common presenting sign in children with continuous spike waves during slow-wave sleep syndrome is increasing seizure frequency. Levetiracetam is effective in treating children with continuous spike waves during slow-wave sleep syndrome. However, the relapse rate of continuous spike waves during slow-wave sleep syndrome remains high in young children.

A psychometric study of the Bayley Scales of Infant and Toddler Development - 3rd Edition for term and preterm Taiwanese infants

The Bayley Scales of Infant and Toddler Development - 3rd Edition (Bayley-III) was updated to enhance its usefulness for contemporary child developmental assessment. However, recent data in Western countries have implicated the overestimation of child development by the new instrument. This study aimed to investigate the psychometric features of the Bayley-III for term and preterm infants in Taiwan. Forty-seven term infants and 167 preterm infants were prospectively examined with the Bayley Scales of Infant Development - 2nd Edition (BSID-II) and the Bayley-III at 6, 12, 18, and 24 months of age (corrected for prematurity). The psychometric properties examined included reliability, construct validity, and known-group validity. The intra- and inter-rater reliabilities of the Bayley-III were good to excellent. The correlations between the BSID-II and Bayley-III raw scores were good to excellent for the cognitive and motor items and low to excellent for the language items. Term infants achieved higher composite scores than preterm infants on all of the Bayley-III scales (p<0.05). However, their rates of developmental delay were lower than the previously established prevalence estimates. The Bayley-III cut-off composite score was adjusted 10-20, 1-13, and 12-24 points higher than 70 for optimal prediction of cognitive, language, and motor delay, respectively, as defined by the BSID-II index score<70. The Bayley-III is a reliable instrument that extends its previous edition, especially in early language assessment. However, the upward adjustment of its cut-off score is recommended for the accurate identification of developmental delay in term and preterm Taiwanese infants.