Markedly elevated serum biotinidase activity may indicate glycogen storage disease type Ia.

We report two children who presented with symptoms suggestive of biotinidase deficiency. Rather than deficiency, markedly elevated serum biotinidase activities were found. Based upon literature reports of elevated biotinidase activities in children with glycogen storage disease (GSD) type Ia, we considered the latter in our differential diagnosis and subsequently confirmed GSD type Ia in both patients by enzymatic testing. GSD type Ia should be considered in children with markedly elevated serum biotinidase activity.

GABA receptor antagonists modulate postmitotic cell migration in slice cultures of embryonic rat cortex.

Recent studies indicate that GABA acts as a chemoattractant during rat cortical histogenesis. In vivo, GABA localizes in appropriate locations for a chemoattractant, along migratory routes and near target destinations for migrating cortical neurons. In vitro, GABA induces dissociated embryonic cortical neurons to migrate. Here, embryonic rat cortical slices were cultured in the presence or absence of GABA receptor (GABA-R) antagonists to assess GABA's effects on neuronal migration in situ. Gestational day 18 (E18) cortical slices were incubated overnight in bromodeoxyuridine (BrdU)-containing medium to label ventricular zone (vz) cells as they underwent terminal mitosis. The slices were then cultured in BrdU-free medium with or without GABA-R antagonists. In control slices, most BrdU(+) cells were observed in the cortical plate (cp) after 48 h. In contrast, cultures maintained in either saclofen (a GABA(B)-R antagonist) or picrotoxin (a GABA(A/C)-R antagonist) had few BrdU-labeled cp cells. However, the effects of the two antagonists were distinct. In the picrotoxin-treated slices, nearly half of all BrdU(+) cells remained in the vz and subventricular zone (svz), whereas saclofen treatment resulted in an accumulation of BrdU(+) cells in the intermediate zone (iz). Bicuculline, a GABA(A)-R antagonist, did not block, but rather enhanced migration of BrdU(+) cells into the cp. These results provide evidence that picrotoxin-sensitive receptors promote the migration of vz/svz cells into the iz, while saclofen-sensitive receptors signal cells to migrate into the cp. Thus, as cortical cells differentiate, changing receptor expression appears to modulate migratory responses to GABA.

Glutamate acting at NMDA receptors stimulates embryonic cortical neuronal migration.

During cortical development, embryonic neurons migrate from germinal zones near the ventricle into the cortical plate, where they organize into layers. Mechanisms that direct neuronal migration may include molecules that act as chemoattractants. In rats, GABA, which localizes near the target destination for migrating cortical neurons, stimulates embryonic neuronal migration in vitro. In mice, glutamate is highly localized near the target destinations for migrating cortical neurons. Glutamate-induced migration of murine embryonic cortical cells was evaluated in cell dissociates and cortical slice cultures. In dissociates, the chemotropic effects of glutamate were 10-fold greater than the effects of GABA, demonstrating that for murine cortical cells, glutamate is a more potent chemoattractant than GABA. Thus, cortical chemoattractants appear to differ between species. Micromolar glutamate stimulated neuronal chemotaxis that was mimicked by microM NMDA but not by other ionotropic glutamate receptor agonists (AMPA, kainate, quisqualate). Responding cells were primarily derived from immature cortical regions [ventricular zone (vz)/subventricular zone (svz)]. Bromodeoxyuridine (BrdU) pulse labeling of cortical slices cultured in NMDA antagonists (microM MK801 or APV) revealed that antagonist exposure blocked the migration of BrdU-positive cells from the vz/svz into the cortical plate. PCR confirmed the presence of NMDA receptor expression in vz/svz cells, whereas electrophysiology and Ca2+ imaging demonstrated that vz/svz cells exhibited physiological responses to NMDA. These studies indicate that, in mice, glutamate may serve as a chemoattractant for neurons in the developing cortex, signaling cells to migrate into the cortical plate via NMDA receptor activation.

Catastrophic metabolic encephalopathies in the newborn period. Evaluation and management.

The newborn who presents with neurologic symptoms such as seizures or lethargy due to inborn error of metabolism is an important problem. Although each inborn error that presents in this manner is rare, these conditions are not rare as a group, and more than one in 1000 babies is affected with one of the more than 100 different inborn errors that are now known. Many of these conditions present with much the same features seen in sepsis or asphyxia and, when untreated, can lead rapidly to death or permanent neurologic damage. Early diagnosis and management may prevent some or all of this morbidity, and also permits the parents to be informed about the chances of having other affected children. Despite the large number and complexity, most metabolic encephalopathies can be diagnosed by applying a few simple clinical principles and laboratory tests. These principles, and the typical features of some inborn errors that present in the neonate, are detailed in this article.

Treatment of Smith-Lemli-Opitz syndrome: results of a multicenter trial.

Patients with the RSH or Smith-Lemli-Optiz syndrome (SLOS) have an inborn error of cholesterol biosynthesis which results in a deficiency of cholesterol and an elevation of the cholesterol precursor, 7-dehydrocholesterol. A treatment protocol consisting of administration of cholesterol +/- bile acids was initiated in an attempt to correct the biochemical abnormalities seen. Fourteen patients (8 female, 6 male: ages 2 months to 15 years) have now been treated for 6-15 months. Three patients received cholesterol alone, while 11 patients received cholesterol and one or more bile acids. Biochemical improvement in sterol levels and in the ratio of cholesterol to total sterols was noted in all patients. The most marked improvement was noted in patients presenting with initial cholesterol levels < 40 mg/dl. No toxicity was observed. Clinical improvement in growth and neurodevelopmental status was also observed.

Radiocephalometric evaluation of a family with mandibulofacial dysostosis.

Persons from four generations of a family with mandibulofacial dysostosis (MFD), known as Treacher Collins (TC) Syndrome, were examined for the presence of clinical signs traditionally associated with this syndrome. In this family, 14 adults, who had been judged trait bearers by an earlier family study were included in this study. Maxillary and mandibular study models were taken of affected and unaffected family members. Panoramic cephalograms and lateral radiographs were taken. The lateral cephalograms were traced and digitized on a computer system and compared. The 117 cephalometric values of the trait bearers were compared with known standard values and nontrait bearing family members. In the trait bearing group, 81 of the 117 values and, in the nontrait bearing group, 72 of the 117 values were significantly different (p < 0.05) when comparing mean values to the accepted normal range. The interfamily comparison between trait-bearing and nontrait members revealed nine values to be significantly different. This indicates that cephalometric analysis of these patients, some of whom have minimal clinical expression of the gene, may have potential value for screening and further characterization of this condition. The results also suggest that intrafamily comparisons may be of greater value for diagnostic confirmation of TC than comparison with literature norms.

Intrafamilial variability in Hurler syndrome and Sanfilippo syndrome type A: implications for evaluation of new therapies.

Intrafamilial variability has not been reported previously in Hurler syndrome or Sanfilippo syndrome type A. We describe two families in which sibs with comparable deficiencies of alpha-iduronidase (Hurler) or sulfamidase (Sanfilippo type A) activities in vitro nonetheless have divergence in clinical severity and disease progression. These cases underscore the need for caution in counseling as well as the limitations of using sibs as controls in evaluating the outcome of treatment.

Molybdenum cofactor deficiency.

We describe a new case of molybdenum cofactor deficiency, an underrecognized inborn error of metabolism that results in neonatal seizures and neurologic abnormalities. Characteristic biochemical defects in affected individuals include hypouricemia, elevated urine sulfate (detectable by dipstick), and elevated S-sulfocysteine (detectable by anion exchange chromatography). This disorder should be considered in the differential diagnosis of neonatal seizures.

Mutation in the 4a-carbinolamine dehydratase gene leads to mild hyperphenylalaninemia with defective cofactor metabolism.

Hyperphenylalaninemias represent a major class of inherited metabolic disorders. They are most often caused by mutations in the phenylalanine hydroxylase gene and, less frequently but with usually more serious consequences, in genes necessary for the synthesis and regeneration of the cofactor, tetrahydrobiopterin. This cofactor is absolutely required for all aromatic amino acid hydroxylations, and, recently, nitric oxide production from L-arginine has also been found to be dependent on tetrahydrobiopterin. Phenylalanine hydroxylase catalyzes a coupled reaction in which phenylalanine is converted to tyrosine and in which tetrahydrobiopterin is converted to the unstable carbinolamine, 4a-hydroxytetrahydrobiopterin. The enzyme, carbinolamine dehydratase, catalyzes the dehydration of the carbinolamine to quinonoid dihydropterin. A decreased rate of dehydration of this compound has been hypothesized to be responsible for the production of 7-biopterin found in certain mildly hyperphenylalaninemic individuals. We have now identified nonsense and missense mutations in the 4a-carbinolamine dehydratase gene in a hyperphenylalaninemic child who excretes large amounts of 7-biopterin. This finding is consistent with the role of the carbinolamine dehydratase in the phenylalanine hydroxylation reaction. Together with previously identified inherited disorders in phenylalanine hydroxylase and dihydropteridine reductase, there are now identified mutations in the three enzymes involved in the phenylalanine hydroxylation system. In addition, the genetics of this system may have broader implications, since the product of the dehydratase gene has previously been shown to play an additional role (as dimerization cofactor for hepatocyte nuclear factor-1 alpha) in the regulation of transcription, through interaction with hepatocyte nuclear factor-1 alpha.

Update on inborn errors of metabolism: primary lactic acidemia.

Initially thought to be rare, primary lactic acidemia is diagnosed with increasing frequency. Elevations in lactate and pyruvate are markers for a variety of metabolic blocks. Although there have been great strides made in the diagnosis and treatment of lactic acidemia, much remains to be learned. As laboratory techniques improve, clinicians will be able to make an exact enzymatic diagnosis on an increasing percentage of patients. Specific enzymatic diagnosis also will help clinicians determine inheritance patterns, recurrence risks, and methods of prenatal diagnosis.

Hyperuricemia in medium-chain acyl-coenzyme A dehydrogenase deficiency.

Six infants and children with medium-chain acyl-coenzyme A dehydrogenase deficiency were found to have hyperuricemia during an acute episode. Hyperuricemia may be a clue to the diagnosis of medium-chain acyl-coenzyme A dehydrogenase deficiency.