Antihypertensive treatment during pregnancy and functional development at primary school age in a historical cohort study.

OBJECTIVE: To determine the functional development of children born after treatment of mild-to-moderate gestational hypertension with labetalol versus methyldopa, and no antihypertensive treatment. DESIGN: Historical cohort study. SETTING: Twelve Dutch hospital departments of obstetrics. POPULATION: Live-born children born in these hospitals and prenatally exposed to labetalol, methyldopa, or bed rest because of mild-to-moderate gestational hypertension. METHODS: Central nervous system development was measured with standard tests at 4-10 years of age. Linear regression techniques and Pearson's chi-square tests were used to compare the groups with regard to the outcome measures. MAIN OUTCOME MEASURES: Intelligence quotient (IQ), concentration, motor development, and behaviour at primary school age. RESULTS: A total of 202 children were included in the analyses. More children exposed to labetalol had attention deficit hyperactivity disorder (ADHD) than those exposed to methyldopa (OR 2.3; 95% CI 0.7-7.3), or those born to women who had been admitted for bed rest (OR 4.1; 95% CI 1.2-13.9). Sleeping problems seemed to be reported more frequently after prenatal methyldopa exposure than after exposure to labetalol (OR 3.2; 95% CI 0.6-16.7) or bed rest (OR 4.5; 95% CI 0.9-23.2), although the differences were not statistically significant. Test scores on other aspects of functional development did not differ between the three groups. CONCLUSIONS: In this hypothesis-generating study, labetalol exposure in utero seemed to increase the risk of ADHD among children of primary school age, whereas prenatal methyldopa exposure might influence sleep. Further studies with appropriate sample sizes are warranted to determine the long-term effects of antihypertensive medications.

Distal spinal muscular atrophy as a major feature in adult-onset ataxia telangiectasia.

The authors report four adult-onset ataxia telangiectasia (AT) patients belonging to two families lacking pronounced cerebellar ataxia but displaying distal spinal muscular atrophy. AT was proven by genetic studies showing ATM mutations and a reduced level of ATM. ATM activity, as measured by phosphorylation of p53, was close to normal, indicating that the p53 response is not the only factor in preventing neural damage in anterior horn cells in AT.

Histology of hereditary neuralgic amyotrophy.

We report the findings in five muscle and three sural nerve biopsies, and in one postmortem plexus specimen, from six patients with hereditary neuralgic amyotrophy (HNA). We found that the sensory nerves are definitely involved in HNA despite the mainly motor symptoms, and that lesions in nerves and muscles are more widespread throughout the peripheral nervous system than clinically presumed, but, simultaneously, very focally affect isolated fascicles within individual nerves.

Botulinum toxin effect on salivary flow rate in children with cerebral palsy.

OBJECTIVE: To investigate the effectiveness of botulinum neurotoxin (BoNT) type A in reducing salivary flow rate in children with cerebral palsy (CP) with severe drooling. METHODS: During a controlled clinical trial, single-dose BoNT injections into the submandibular salivary glands were compared with scopolamine treatment. Forty-five school-aged children were included. Salivary flow rates from all major glands were obtained at baseline and compared with measurements during the interventions. Basic statistics consisted of analysis of difference scores. RESULTS: Compared with baseline, the mean decrease in submandibular flow was 25% during scopolamine and 42% following BoNT injections. The difference scores were significant with maximum reductions 2, 4, and 8 weeks following BoNT. Of all children, 95% responded during scopolamine. Response rates for BoNT were significantly lower and varied from 69% at 2 weeks to 49% at 24 weeks after injection (the end of the study). Four patients discontinued scopolamine therapy because of side effects. Only incidentally mild side effects were reported from BoNT. CONCLUSIONS: Intraglandular BoNT injections significantly reduce salivary flow rate in the majority of drooling CP children, demonstrating high response rates up to 24 weeks. The procedure is simple to perform, effective, and safe when ultrasound guidance is used. The anticholinergic effect of BoNT exceeds that of scopolamine. As anticholinergic drugs are frequently contraindicated because of side effects, BoNT injections offer an alternative in the treatment of drooling.

A systematic review for evidence of efficacy of anticholinergic drugs to treat drooling.

Drooling frequently occurs in children with multiple handicaps; application of anticholinergic drugs is a potential strategy to treat drooling. A computer aided search of original studies concerning the treatment of drooling was carried out. The methodological and statistical integrity of the identified studies were assessed with previously defined criteria. The articles were weighed for their separate contribution to the evidence. The search resulted in 64 reports, of which seven studies passed the screening and were subjected to further assessment and discussion by three referees. Because of the small number of reports and the methodological restriction within the studies, no meta-analysis could be performed. No general conclusion could be made about the efficacy of anticholinergic drugs in treatment of drooling in children with multiple handicaps. There was some evidence that three anticholinergic drugs (benztropine, glycopyrrolate, and benzhexol hydrochloride) are effective in the treatment of drooling, but it could not be concluded that one drug is preferable.

Nijmegen breakage syndrome: a neuropathological study.

Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder, due to defects in the NBS1 gene and belongs to the DNA repair disorders. We report neuropathological findings of the first ever recognised case of the about 60 described cases of NBS. This patient showed severe microcephaly with a simplified gyral pattern especially in the frontal lobes. There were no signs of a degenerative disease, or of a primary migration disorder. A bulge on top of the corpus callosum, most probably a very large remnant of the involuting striae longitudinales mediales et laterales, was found. This can be considered as an incomplete development of limbic structures. The severe diminishment of neocortical neurones suggests an important role for the NBS1 gene in corticogenesis in man, as suggested earlier in animal studies of other DNA-repair genes.

Hereditary neuropathy with liability to pressure palsies with a small deletion interrupting the PMP22 gene.

Hereditary neuropathy with liability to pressure palsies is associated with a deficiency in the Peripheral Myelin Protein 22 (PMP22). Most hereditary neuropathy with liability to pressure palsies cases are caused by a deletion of a 1.5 Mb region on chromosome 17p11.2-12 encompassing the PMP22 gene. We describe a hereditary neuropathy with liability to pressure palsies family that lacks the common deletion, but carries a small deletion spanning the 3' region of the PMP22 gene, causing only a partial deletion of one copy of the gene.

MECP2 mutation in a boy with severe neonatal encephalopathy: clinical, neuropathological and molecular findings.

We describe the clinical and neuropathological presentation of a male with an MECP2 mutation whose sister has Rett syndrome (RS). He presented with severe neonatal encephalopathy and died at the age of 13 months. Mutation analysis of the MECP2 gene demonstrated a 488 - 489 del mutation in his and his sister's copies of the gene. Post mortem examination revealed bilateral polymicrogyria in the perisylvian region. This malformation was visibly more severe than previously described in females with RS and another male with an MECP2 mutation. As bilateral polymicrogyria was described in congenital perisylvian syndrome, the presented patient could be regarded as having suffered from a severe form of this syndrome. We conclude that MECP2 screening should be considered in males with severe neonatal encephalopathy and in males and females with a bilateral polymicrogyria syndrome.

Botulinum toxin A: a new option for treatment of drooling in children with cerebral palsy. Presentation of a case series.

UNLABELLED: Drooling beyond the age of 4 years is pathological, particularly if it occurs in children with neurological and developmental impairment and disability. Considering the therapeutic spectrum of botulinum toxin A and in view of the innervation of the salivary glands, we postulated that intraglandular injections into the submandibular glands with botulinum toxin A could reduce the secretion of saliva and consequently decrease drooling. Three patients with cerebral palsy and severe drooling were selected and evaluated over a 4-month period. Under ultrasound guidance, one dose of botulinum toxin A was injected bilaterally into the submandibular glands. Saliva secretion was measured at baseline and repeated four times during the following 4 months. In the three patients, maximal salivary flow rate of the sublingual and submandibular glands was reduced by 51% to 63%. The time of the maximal effect differed among the three children. The parents reported a satisfactory reduction of drooling throughout the whole study period. No objectionable disturbances of oral functions were observed. There was mild transient thickening of saliva in one of the patients. CONCLUSION: The application of botulinum toxin A to the submandibular gland is a promising technique to reduce salivary flow rate and probably an alternative in the treatment of drooling in children with cerebral palsy.

Scheie syndrome presenting as myopathy.

We investigated two brothers with Scheie syndrome whose only complaint was exercise intolerance. In the quadriceps muscle biopsy of both patients, between the normal muscle fibres an increased number of markedly swollen periodic acid-Schiff-positive fibroblasts were seen. Ultrastructurally, these cells showed an accumulation of enlarged lysosomes, partly filled with electro-dense material. We hypothesize that the accumulation of pathological fibroblasts may interfere with intramuscular force transmission resulting in exercise intolerance.

Clinical, biochemical and molecular genetic characteristics of 19 patients with the Sjögren-Larsson syndrome.

Sjögren-Larsson syndrome (SLS) is an autosomal recessively inherited neurocutaneous disorder caused by a deficiency of the microsomal enzyme fatty aldehyde dehydrogenase (FALDH). We report the clinical characteristics and the results of molecular studies in 19 SLS patients. Patients 1-17 show the classical triad of severe clinical abnormalities including ichthyosis, mental retardation and spasticity. Most patients were born preterm, and all patients exhibit ocular abnormalities and pruritus. Electro-encephalography shows a slow background activity, without other abnormalities. MRI of the brain shows an arrest of myelination, periventricular signal abnormalities of white matter and mild ventricular enlargement. Cerebral (1)H-MR spectroscopy reveals a characteristic, abnormal lipid peak. The degree of white matter abnormality in the MRIs and the height of the lipid peak in (1)H-MR spectra do not correlate with the severity of the neurological signs. The clinical presentation and the clinical course is strikingly similar in these patients. Patient 18 shows a mild phenotype that essentially contains the same, but less severe, clinical features. Patient 19 exhibits the typical, but very mild, dermatological and ocular abnormalities, without any clinical neurological involvement. The diagnosis of SLS was confirmed by demonstration of the enzyme defect in cultured skin fibroblasts. Furthermore, as might be predicted from the essential role of FALDH in leucotriene B(4) (LTB(4)) metabolism, elevated urinary concentrations of LTB(4) and 20-OH-LTB(4) were found in all patients studied. Molecular studies of the FALDH gene revealed eight different mutations, including three new ones: a large 26-base pair deletion (21-46del), a missense mutation (80C-->T) and an insertion mutation (487-488insA). The vast majority of SLS patients seem to be severely affected independent of their genotype.

[Development and developmental disorders of the human brain. III. Neuronal migration disorders of the cerebrum]. / Ontwikkeling en ontwikkelingsstoornissen van het humane brein. III. Neuronale migratiestoornissen van de grote hersenen.

Neuronal migration disorders of the cerebral cortex form a heterogeneous group of abnormalities, characterised by mental retardation, epilepsy and hypotonia. They are prevalent in 1% of the population and in 20-40% of the untreatable forms of epilepsy. Disorders at the start of the migration result in nodular heterotopias. Bilateral periventricular nodular heterotopias are X-linked disorders, in which cortical neurons are unable to leave their position at the ventricular surface due to the absence of filamin 1. The large group of lissencephalies can be divided into a number of syndromes, each of which is characterised by a gene mutation (LIS1, DCX, RELN). These mutations result in agyria and pachygyria, which are characteristic for this group. A number of these abnormalities, especially the smaller nodular heterotopias and focal cortical dysplasia, may be treated by neurosurgical excision.

[Development and developmental disorders of the human brain. II. Development of the cerebral cortex and major tract systems]. / Ontwikkeling en ontwikkelingsstoornissen van het humane brein. II. Ontwikkeling van de hersenschors en de grote baansystemen.

In the development of the cerebral cortex, two phases can be distinguished: (a) the formation of the preplate, a superficial layer essential for a normal lamination of the cerebral cortex; (b) the formation of the cortical plate. The cortical plate divides the preplate into a superficial marginal zone (the future layer I) and the subplate. The transient subplate is important for the formation of thalamocortical projections. Most cortical neurons arise in the ventricular zone of the pallium and migrate along radial glial cells (radial migration) to the cortical plate. The gamma-aminobutyric acid (GABA)ergic cortical interneurons, however, originate from the ganglionic eminences and reach the cerebral cortex through tangential migration.

Decreased immunoglobulin class switching in Nijmegen Breakage syndrome due to the DNA repair defect.

Nijmegen breakage syndrome (NBS) is a rare chromosomal-instability syndrome associated with defective DNA repair. Approximately 90% of NBS patients are homozygous for a truncating mutation of the NBS1 gene. As development of the immune system relies on recombination, which involves repair of DNA breaks, one might predict that mutations in the NBS1 gene could cause immunodeficiency. We immunologically investigated the world's largest series of NBS patients (n = 74), confirmed immunodeficiency, and found a discrepancy between relatively normal IgM concentrations, and decreased IgG and IgA concentrations. In addition, a significant relation between low IgA and low IgG levels was found. These data are compatible with a defective class switching in NBS and can be explained by a role of the NBS1 protein in DNA repair, signal transduction, cell cycle regulation or apoptosis.

Cerebrotendinous xanthomatosis: the spectrum of imaging findings and the correlation with neuropathologic findings.

PURPOSE: To describe imaging findings and their neuropathologic correlate in patients with cerebrotendinous xanthomatosis (CTX). MATERIALS AND METHODS: Computed tomographic (CT) and magnetic resonance (MR) images in 24 patients with symptoms (mean age at time of imaging, 37 years; mean disease duration, 18 years) were reviewed for site and frequency of brain, spinal cord, and Achilles tendon involvement. Two patients died, and imaging findings were compared with postmortem neuropathologic findings. RESULTS: Apart from nonspecific supratentorial atrophy and deep white matter changes, more typical hyperintense lesions were seen on T2-weighted images in the dentate nucleus (in 79% of patients), globus pallidus, substantia nigra, and inferior olive and extended into adjacent white matter as disease progressed. In these locations, lipid crystal clefts and perivascular macrophages, neuronal loss, demyelination, fibrosis, and reactive astrocytosis were found at microscopic examination. Hypointensity was sometimes found on T2-weighted images in the dentate nucleus and was related to deposition of hemosiderin and calcifications. CT depicted fewer lesions; all had low attenuation, except for the calcifications. Spinal cord MR imaging revealed increased signal intensity in the lateral and dorsal columns on T2-weighted images. Achilles tendon xanthomas displayed intermediate signal intensity on T1- and T2-weighted images. CONCLUSION: The typical pattern of MR imaging findings reflects the classic histopathologic findings and should prompt the diagnosis of CTX.

A de novo missense mutation in a critical domain of the X-linked DDP gene causes the typical deafness-dystonia-optic atrophy syndrome.

We report the first de novo mutation in the DDP gene in a Dutch 11-year-old boy with deafness and dystonia. Previously reported mutations in the DDP gene have all been frameshifts/nonsense mutations or deletion of the entire gene as part of a larger deletion encompassing the BTK gene. The clinical presentation was uniformly characterised by sensorineural hearing loss, dystonia, mental deterioration, paranoid psychotic features, and optic atrophy, indicating progressive neurodegeneration. Our report illustrates that de novo mutations occur and that a missense mutation, C66W, may cause an equally severe clinical picture. The diagnosis of sensorineural hearing impairment associated with neurologic and visual disability in a male, therefore, should encourage the search for mutations in the DDP gene, even in sporadic cases. The association of deafness-dystonia syndrome with a missense mutation provides valuable information for in vitro investigations of the functional properties of the deafness-dystonia peptide which was recently shown to be the human homolog of a yeast protein, Tim8p, belonging to a family of small Tim proteins involved in intermembrane protein transport in mitochondria.

Cerebrotendinous xanthomatosis. Controversies about nerve and muscle: observations in ten patients.

Neuromuscular characteristics were documented in ten patients with biochemically and genetically confirmed cerebrotendinous xanthomatosis. An array of genotypes was found in these patients. Only one patient complained of muscle weakness, while clinical signs of peripheral neuropathy were present in six patients. Electromyogram showed predominantly axonal neuropathy in seven patients. Neurogenic changes were seen in muscle biopsies of nine patients. Sural nerve biopsies of three patients showed features of axonal neuropathy. In addition, in one patient, extensive onion bulb formation was seen, which is indicative of a primarily demyelinating process. Five patients had normal mitochondrial respiratory chain enzyme activity. It is concluded that myopathy is not a feature of cerebrotendinous xanthomatosis and that the most prominent neuromuscular abnormality is sensorimotor axonal polyneuropathy.

Congenital fibre type disproportion a time-locked diagnosis: a clinical and morphological follow-up study.

This is the first report that describes the clinical and histological findings in a patient suffering from pure congenital fibre type disproportion (CFTD), who had two biopsies with an interval of 16 years. Additionally, we compared the clinical signs and symptoms of the present case to those of 35 CFTD cases reviewed from the literature. From this we conclude that smallness of type I fibre diameter is not a characteristic feature during the course of pure CFTD. This suggests that CFTD is a time-locked diagnosis.