Remarkable recovery in an infant presenting with extensive perinatal cervical cord injury.

Cervical-cord damage is a complication of a difficult delivery, and results in spinal shock with flaccidity progressing to spastic paralysis. Conventionally, outlook for such patients is extremely poor and most will recover only slightly from quadriplegia and autonomic dysfunction. Here, we report a case in which the extent of damage considerably contrasted with the outcome and recovery. A full-term baby girl born by difficult vaginal delivery displayed bilateral flaccid paralysis of the lower limbs with absent spontaneous movements, weakness of both upper limbs, hyporeflexia in all limbs and axial hypotonia. MRI of cervicothoracic spine exhibited raised signal intensity in the dorsal aspects of C7 to T1 signifying myelopathy. MRI at 4 months revealed a near-total transection of the cervical cord. However, at 6 months, the child could move all lower limbs independently with a marked increase in power. There was no spasticity, wasting or incontinence. Reflexes had also returned.

Polymeric nanoparticles containing conjugated phospholipase A2 for nonviral gene delivery.

Polyethylenimine (PEI) was conjugated to phospholipase A(2) (PLA(2)) in an effort to improve transfection efficiency. PLA(2) was conjugated to PEI using EDC as a coupling reagent. The activity of enzyme in the conjugate was measured. DNA condensation ability of the conjugate to polymer was determined. The resultant nanoparticles were characterized by dynamic and electrophoretic light scattering. Two reporter genes were used to evaluate transfection efficiency in human embryonic kidney (HEK293) and human hepatoma (HepG2) cell lines. Conjugate was shown to retain PLA(2) activity and its ability to condense plasmid DNA, resulting in nanoparticles of a similar size to native PEI. The results demonstrated at N/P ratios of 15 and 20 showed 13- and 8-fold increase in transfection efficiency, respectively, compared to the maximum transfection efficiency of PEI (N/P ratio of 5) in the whole range of N/P ratios tested, from 5 to 60 in HepG2 cells. Toxicity studies in HepG2 cells showed uncomplexed conjugate had similar toxicity as PEI, and when complexed with DNA the conjugate had a significantly reduced toxicity. The results clearly indicate the potential for this approach to improve efficiencies of nonviral gene delivery vectors.

Evaluation of the transfection property of a peptide ligand for the fibroblast growth factor receptor as part of PEGylated polyethylenimine polyplex.

PURPOSE: Experiments were conducted to evaluate the utility of a peptide receptor ligand to improve transfection efficiency as part of a polyethylenimine-polyethylene glycol (PEI-PEG) polyplex. The 7-mer peptide (MQLPLAT), targeted toward the fibroblast growth factor 2 (FGF2) receptor, was recently identified using a phage-display library method as possessing a high degree of specificity for the FGF2 receptor without the mutagenicity associated with FGF itself. Two approaches (pre-modification or post-modification) to incorporate the peptide into the PEGylated polyplex were compared in terms of their effect on particle size, surface charge, DNA condensation ability, toxicity, cellular uptake and transfection efficiency. METHODS: The peptide was conjugated to branched PEI (25 kDa) via a PEG spacer either before (pre-modified) or after (post-modified) complexation of PEI with DNA. Polyethyleneimine was conjugated to the PEG spacer (N-hydroxy succinimide (NHS) -PEG-maleimide (Mal)) through the NHS group. The FGF2 peptide was synthesized to contain a cysteine at the carboxyl end (MQLPLATC) and conjugated to the PEG spacer via the Maleimide group. Conjugates were evaluated using (1)H NMR, amino acid analysis, and picrylsulfonic acid assay. DNA condensation was evaluated using agarose gel electrophoresis and cellular toxicity was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cellular uptake was measured using flow cytometry and transfection efficiency was determined using a luciferase reporter gene assay. RESULTS: Both pre- and post-modification approaches led to a decrease in the zeta potential of the resulting polyplexes but did not alter their size. The pre-modification of PEI did not affect its ability to condense DNA. However, polyplexes formed with the pre-conjugated PEI did not improve cell uptake or transfection efficiency. In contrast, polyplexes that were post-modified with the FGF2 peptide resulted in a 3-fold increase in cell uptake and a 6-fold increase in transfection efficiency. Both pre- and post-modified polyplexes resulted in lower toxicity compared with unmodified PEI. CONCLUSIONS: The results indicate that the FGF2 peptide improves transfection efficiency when used as part of post-modified PEI/PEG polyplex. When used with pre-modified PEI/PEG, the beneficial effect of the peptide on transfection is not evident, probably because, in this case, the peptide ligand is not readily accessible to the FGF receptor.

A novel locus for hereditary spastic paraplegia with thin corpus callosum and epilepsy.

BACKGROUND: Hereditary spastic paraplegia (HSP) are classified clinically as pure when progressive spasticity occurs in isolation or complicated when other neurologic abnormalities are present. At least 22 genetic loci have been linked to HSP, 8 of which are autosomal recessive (ARHSP). HSP complicated with the presence of thin corpus callosum (HSP-TCC) is a common subtype of HSP. One genetic locus has been identified on chromosome 15q13-q15 (SPG11) for HSP-TCC, but some HSP-TCC families have not been linked to this locus. METHODS: The authors characterized two families clinically and radiologically and performed a genome-wide scan and linkage analysis. RESULTS: The two families had complicated ARHSP. The affected individuals in Family A had thin corpus callosum and mental retardation, whereas in Family B two of three affected individuals had epilepsy. In both families linkage analysis identified a locus on chromosome 8 between markers D8S1820 and D8S532 with the highest combined lod score of 7.077 at marker D8S505. This 9 cM interval located on 8p12-p11.21 represents a new locus for ARHSP-TCC. Neuregulin and KIF13B genes, located within this interval, are interesting functional candidate genes for this HSP form. CONCLUSION: Two consanguineous families with complicated autosomal recessive hereditary spastic paraplegia were clinically characterized and genetically mapped to a new locus on 8p12-p11.21.

Targeted polymers for gene delivery.

Over the past decade, significant research has been done in the area of polymer-mediated gene delivery. Synthesis of new polymers and modifications to existing polymers has resulted in polyplexes with improved in vitro and in vivo transfection efficiencies. Targeting has been an important aspect of this research, and various strategies for obtaining selective and enhanced gene delivery to the target site have been evaluated. This review covers the different aspects involved in polyplex targeting. Development of targeted polyplexes involves a careful consideration of the target site, the targeting ligand and the physicochemical properties of the polyplex itself. The need to redirect the polyplexes by using the 'shield and target' approach by reducing nonspecific interactions with negatively charged components, while conferring specificity by incorporating targeting ligands, is discussed. Basic chemistry involved in modifying polymers is covered and examples of targeting strategies used for tissue-specific gene delivery are discussed. Targeting is also discussed in the broader context of developing safe and effective polymeric vectors for in vivo gene delivery. Maximum benefit of targeting can be obtained when it is used as part of a multi-functional complex containing elements designed to improve gene delivery and reduce overall toxicity of the polyplex.

Risperidone treatment in 12 children with developmental disorders and attention-deficit/hyperactivity disorder.

BACKGROUND: Risperidone is a novel antipsychotic drug that has been tried in the treatment of several child psychiatric disorders. In an open clinical study, we evaluated the safety and efficacy of risperidone in children with developmental disorder and behavioral problems including attention-deficit/hyperactivity disorder (ADHD). METHOD: Twelve patients aged 4 to 14 years who had a DSM-IV-diagnosed developmental disorder and ADHD in addition to other behavioral problems, in particular aggression, were treated with risperidone for a period of up to 2 years with daily doses ranging from 1 to 3 mg. Data were gathered from December 2002 to December 2004. RESULTS: A positive clinical response was noted in 9 of the 12 patients within 3 months of study recruitment according to the Clinical Global Impressions-Improvement scale. Risperidone was well tolerated by all 12 patients. The most commonly reported side effect was sedation, which necessitated dosage reduction in 2 patients, but not discontinuation. CONCLUSIONS: Our findings suggest that risperidone may be an effective and safe treatment for children and adolescents with developmental disorder and disruptive behaviors.

Four novel mutations in patients from the Middle East with the infantile form of GM1-gangliosidosis.

GM1-gangliosidosis is a lysosomal storage disorder caused by a deficiency of beta-galactosidase. It is mainly characterized by progressive neurodegeneration and in its most severe infantile form it leads to death before the age of four. We have performed molecular analysis of five patients with the infantile form of GM1-gangliosidosis originating from the Middle East (two from Saudi Arabia and three from the United Arab Emirates). We have identified four novel mutations and one previously reported mutation in the GLB1 gene. The first novel mutation found in the homoallelic state in a patient from Saudi Arabia, is a c.171C>G transversion in exon 2 which creates a premature stop codon. Northern blot analysis in fibroblasts from the patient showed no mRNA and expression studies in COS-1 cells showed complete absence of the 85kDa precursor protein and no catalytic activity. The second novel mutation is a splicing error in intron 2, c.245+1G>A. This mutation was found in the heteroallelic state in a patient from Saudi Arabia, the second mutation being the previously described c.145C>T mutation. The third novel mutation is a missense mutation in exon 4, c.451G>T, found in the homoallelic state in a patient from the United Arab Emirates. Expression studies of this mutation in COS-1 cells showed complete absence of the 85kDa precursor protein and no catalytic activity. The fourth novel mutation is a splicing mutation in intron 8, c.914+4A>G, found in the homoallelic state in two siblings from the United Arab Emirates. This study has revealed genetic heterogeneity of the beta-galactosidase deficiency in the Arabic population [corrected]

Microcephaly associated with abnormal gyral pattern.

Primary microcephaly is a heterogeneous group of cerebral malformations either with a relatively well-preserved or an abnormal gyral pattern. We describe the MRI findings and clinical features of 14 children with the combination of microcephaly and an abnormal gyral pattern. All children except one were Arabs and nine out of the 14 patients were born to consanguineous parents. Seven patients showed features of a simplified gyral pattern with relatively preserved posterior fossa structures. Two boys had a cortical malformation in the agyria-pachygyria spectrum; one of these two patients showed agenesis of the corpus callosum and severe cerebellar hypoplasia as well. The microcephaly was associated with polymicrogyria and leukoencephalopathy in two patients, with cortical dysplasia and hypogenesis of the corpus callosum in one patient, with agyria-pachygyria with callosal and pontocerebellar dysplasia in one patient, and a simplified gyral pattern with severe cerebellar hypoplasia in one case. One patient died in the neonatal period and three in infancy. All patients, who survived the neonatal period, had developmental delay, intellectual disability, and neurological deficits, and nine suffered from epilepsy.

Frameshift mutation of the zinc finger homeo box 1 B gene in syndromic corpus callosum agenesis (Mowat-Wilson syndrome).

We report a girl who had Hirschsprung disease in association with distinct facial appearance, microcephaly, agenesis of the corpus callosum and mental retardation (Mowat-Wilson syndrome). Mutation analysis of the zinc finger homeo box 1 B (ZFHX1 B) gene revealed a de novo 7 bp deletion (TGGCCCC) at nucleotide 1773 (1773 delTGGCCCC) resulting in a frameshift and leading to a termination codon at amino acid residue 604 (604 X) in exon 8 C. The zinc finger homeo box 1 B (Smad interacting protein-1) is a transcription corepressor of Smad target genes with functions in the patterning of neural crest derived cells, CNS, and midline structures. Mutations in ZFHX1 B can lead to neurological disorders in addition to dysmorphic features, megacolon, and other malformations.

Epilepsy in children with cerebral palsy.

OBJECTIVES: To study the occurrence, associated factors, nature and prognosis of seizures in children with cerebral palsy (CP). DESIGN: A prospective, descriptive, hospital-based, case-control study. SETTING: Tertiary level University Teaching Hospitals in the Al Ain Medical District, United Arab Emirates. PATIENTS: Fifty-six children with CP and seizures seen in the neurodevelopmental clinics at Al Ain and Tawam University Hospitals during the period of 1997-1999 were studied (group 1). Two control groups of 35 children with CP without seizures (group 2) and 50 children with seizures but no CP (group 3) were also studied. RESULTS: Spastic tetraplegia was the commonest type of CP associated with seizures whereas spastic diplegia was the commonest variety of CP in group 2. Most children with CP had an early onset of seizures within the first year of life as against those without CP. The children in group 1 had a higher incidence of neonatal seizures (42.9% vs. 29.4% in group 2 and 0% in group 3), presence of significant developmental delay (98.2% vs. 20.0% in group 3), occurrence of significant abnormalities on brain imaging (94.6% vs. 19.6% in group 3) and a need for use of more than 1 antiepileptic drug (66.1% vs. 30.0% in group 3). Over half of children in the study group presented with generalized tonic clonic seizures; the electroencephalogram (EEG) showed focal epileptic discharges with or without secondary generalization in 39.3%. The overall outcome of seizures in children with CP was poor needing prolonged course of anticonvulsant medications, polytherapy and higher incidence of refractory seizures and admissions for status epilepticus compared to the control group. CONCLUSIONS: Cerebral palsy is associated with a higher incidence of seizure disorders, which, in a majority, has its onset in the neonatal period; brain imaging showed abnormal pathology in most affected children, which possibly accounts for the tendency to more refractory seizures in these children.

Are the strokes in moyamoya syndrome associated with Down syndrome due to protein C deficiency?

Moyamoya syndrome has occasionally been seen in association with Down syndrome. We report a child with moyamoya syndrome and Down syndrome who was admitted with repeated episodes of strokes; his magnetic resonance imaging and magnetic resonance angiography findings confirmed the presence of occlusive cerebrovascular disease with basal collateral vessels. His protein C levels were significantly decreased during the stroke. Complete clinical recovery was seen during follow-up. This raises the possibility of a link between protein C deficiency and Down syndrome with moyamoya syndrome.

CT and MR patterns of hypoxic ischemic brain damage following perinatal asphyxia.

The objectives were to study the clinical and neurological abnormalities in children with cerebral palsy and to attempt to correlate the signs with radiological abnormalities detected by CT scan and/or MRI of the brain. In a prospective, hospital-based study, 65 children with cerebral palsy were examined neurologically and their perinatal history was reviewed. Their cranial CT scan, and/or magnetic resonance images were studied. The association between the gestational ages, perinatal history, neurological deficits, and the radiological appearances were studied. Of the 24 preterm-born and 41 term-born children, 23 had spastic diplegia; 57 per cent of these children has significant periventricular leucomalacia, which was more common among preterm-born children. Of the 13 children with hemiplegia, 12 had unilateral lesions on neuroimaging. Spastic tetraplegia was associated with extensive, bilateral, diffuse brain damage. Extrapyramidal cerebral palsy was far more common among term-born infants and 80 per cent of these showed significant abnormalities in the basal ganglia region. Ataxic cerebral palsy was an uncommon variety and there was no significant correlation between neurological signs and abnormalities on brain imaging. In conclusion, the radiological findings were closely related to the type of cerebral palsy and the neurological deficit except in the ataxic type. We believe that CT and MRI imaging are helpful in understanding the pathology and the timing of the lesion in cerebral palsy.

Predictors of febrile seizure: a matched case-control study.

In a prospective matched case-control study carried out to determine risk factors of febrile seizures among children in the United Arab Emirates, 84 patients with febrile seizure were identified and were matched with 84 control febrile patients without seizure in the same age range, who attended the same hospital during the same period of time. Logistic regression analysis showed that the age at first seizure, family history of febrile seizure, duration of fever, and height of temperature were the only significant predictors for febrile seizures.

External hydrocephalus--a report of 16 cases from Oman.

Sixteen cases of external hydrocephalus (EH) were seen from January 1993 to June 1995. There were 13 (81.3 per cent) male and three female children. Fourteen (87.5 per cent) were under 12 months of age. Three siblings with EH were seen in one family. All but three of the 16 recovered over time without medical or surgical intervention. These three needed cerebral decongestants in the acute phase.