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We report three siblings, who were treated empirically with levodopa combined with carbidopa. There was an immediate therapeutic response. Biochemical investigation surprisingly showed the clinical phenotype to be caused by aromatic L–amino acid decarboxylase deficiency. Molecular characterization showed a homozygous point mutation (c.387 GA) in exon 3. Kinetic studies showed the mutation to decrease the binding affinity for the substrate. This, combined with structural modeling suggesting alteration of active site configuration, provided an explanation for the therapeutic response to levodopa. Ann Neurol 2004

Item does not contain fulltext Aromatic L-amino acid decarboxylase (AADC) is a vitamin B 6 requiring enzyme involved in the biosynthesis of the neurotransmitters dopamine (DA) and serotonin. Lack of AADC leads to a combined deficiency of the catecholamines DA, norepinephrine (NE), epinephrine (E) as well as of serotonin. Here we describe premature twins who presented with severe seizures, myoclonus, rotatory eye movements and sudden clonic contractions. The patients showed an improvement of the clonic contractions under vitamin B 6 supplementation but died in the third week of life. In CSF and urine a biochemical pattern indicative of AADC deficiency was revealed. Concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were decreased, in association with increased concentrations of 3-ortho-methyldopa (3-OMD) in CSF and significantly increased vanillactic acid in urine. The AADC enzyme substrates L-dopa and 5-hydroxytryptophan (5-HTP) were elevated in CSF. Elevated concentrations of threonine as well as of an unidentified compound in CSF rounded off the biochemical pattern. AADC activity was found to be increased in plasma and deficient in the liver. Molecular studies effectively ruled out a genetic defect in the AADC gene. The basis for the epileptic encephalopathy in the twins may be located in the metabolism of vitamin B 6 and remains to be defined.

Item does not contain fulltext Aromatic L-amino acid decarboxylase (AADC - E.C. 4.1.1.28) converts L-dopa to dopamine and 5-hydroxytryptophan to serotonin. Inherited deficiency of this enzyme leads to decreased brain levels of these neurotransmitters. Clinically this results in the development of a progressive neurometabolic disorder characterized by severe hypotonia, dystonic and choreoathetoid movements, oculogyric crises, and hypothermia from infancy. Here we describe the clinical, biochemical and molecular details of two affected brothers, one of whom, despite the lack of AADC, presented with hyperdopaminuria. In addition, we detail his reactions to treatment with dopaminergic agonists, monoamine oxidase inhibitors and pyridoxine.

In previous studies we have reported that preactivated merocyanine 540 (pMC540) and its chemically synthesized isolates merocil and merodantoin mediate their preferential cytotoxicity towards certain types of malignant cells including human breast cancer cells in vitro and in vivo. The mechanism of cytotoxic action appears to be, in part, via initial interaction with topoisomerase II leading to apoptosis. To further build upon these findings we now show that pMC540 and merodantoin disrupt mitochondrial morphology and function in intact MCF-7 human breast cancer cells as seen by their causing the release of rhodamine 123 from prestained cells, a rapid reduction in ATP levels, inhibition of succinate dehydrogenase activity and oxygen consumption. These data suggest that mitochondria may also be an important target for the cytotoxic action of pMC540 and merodantoin mediated through disruption of the energy balance.

We report three siblings, who were treated empirically with levodopa combined with carbidopa. There was an immediate therapeutic response. Biochemical investigation surprisingly showed the clinical phenotype to be caused by aromatic L-amino acid decarboxylase deficiency. Molecular characterization showed a homozygous point mutation (c.387 G--A) in exon 3. Kinetic studies showed the mutation to decrease the binding affinity for the substrate. This, combined with structural modeling suggesting alteration of active site configuration, provided an explanation for the therapeutic response to levodopa.

Item does not contain fulltext Two girls and one boy are described, with severe infantile parkinsonism-dystonia. This syndrome is usually caused by endogenous dopamine deficiency but in these patients was associated with elevated dopamine metabolites in CSF and an unusual eye movement disorder: ocular flutter together with saccade initiation failure. Pyramidal tract signs also emerged in the course of the disease in two patients. This combination of symptoms and biochemical findings suggests a unique pathogenic mechanism.

Aromatic L-amino acid decarboxylase (AADC, EC 4.1.1.28), a vitamin B 6 -requiring enzyme, converts L-dopa into dopamine (DA), and 5-hydroxytryptophan (5-HTP) into serotonin (Figure 1). The enzyme is ubiquitous in nature, occurring in high levels in the cytoplasm of most tissues including liver, stomach, kidney and brain. Lack of AADC leads to a combined deficiency of the neurotransmitters DA, norepinephrine (NE), epinephrine (E) and serotonin. The major biochemical hallmarks of AADC deficiency are increases of L-dopa, 3-O-methyldopa (3-OMD) and 5-HTP in urine, plasma and cerebrospinal fluid (CSF), together with decreased CSF concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) (Abeling et al 2000; Hyland et al 1992a) (Figure 1). L-Dopa and 5-HTP are the substrates for the enzyme and 3-OMD accumulates after the catechol O-methyltransferase-catalysed methylation of L-dopa in a reaction that uses S-adenosylmethionine (SAM) as a methyl donor. In the periphery, 3-OMD is converted into vanillyllactic acid (VLA) and excreted in the urine (Hyland et al 1992a).

Three photoproducts of merocyanine 540 have been isolated, chemically characterized and synthesized. Two of these photoproducts, merocil and merodantoin, show significant antitumor activity in vitro and in vivo while demonstrating minimal toxicity to normal cells and tissues. Treatment of lymphoma cells with these compounds resulted in a rapid decline in macromolecular synthesis, DNA fragmentation inhibitable by actinomycin D and cycloheximide, and a marked rise in intracellular calcium. In vitro analysis revealed that activity of these compounds is dependent on topoisomerase II. These results are discussed in terms of the novel class of topoisomerase II-dependent compounds for potential use in chemotherapy.