Missed initial appointments at Israeli child development centres: Rate, reasons, and associated characteristics.

INTRODUCTION: Missed appointments (MAs) at child development centres (ChDCs) cause multiple problems: they preclude timely diagnosis and treatment of both the invited child and children whose appointment was delayed due to overbooking, as well as disrupting efficient organisational management. The aim of this study was to assess the rate and describe the reasons for missed appointments at Israeli ChDCs, and to evaluate the association of socio-demographic, clinical, and administrative variables with MA rates. METHODS: This nested case-control study included all children scheduled for initial appointments (N = 1143) at three centres during 1 year. Parents of children who missed their appointment and a sample of those who attended were interviewed by telephone. RESULTS: The rate of missed appointments was 26.6%, and the most frequent reasons were unexpected events (26.0%) and lack of insurance coverage (23.4%). Variables associated with lower MA rates were: having had ≥3 types of rehabilitative interventions (odds ratios (OR) = 0.26; 95% confidence interval [CI] 0.16-0.44), detailed referral letter (OR = 0.48; 95%CI 0.30-0.75), telephone reminder (OR = 0.37; 95%CI 0.24-0.57) and health maintenance organisations or private insurance coverage (OR = 0.12; 95%CI 0.06-0.17 and OR = 0.56; 95% CI 0.38-0.89, respectively). CONCLUSION: Encouraging physician's referral letters and personal-contact reminders can reduce missed appointments. Understanding the family's and the child's personal characteristics, and the organisational/administrative aspects of missed appointments may guide efforts to ensure timely care for every child.

EPT1 (selenoprotein I) is critical for the neural development and maintenance of plasmalogen in humans.

Ethanolamine phosphotransferase (EPT)1, also known as selenoprotein 1 (SELENOI), is an enzyme that transfers phosphoethanolamine from cytidine diphosphate-ethanolamine to lipid acceptors to produce ethanolamine glycerophospholipids, such as diacyl-linked phosphatidylethanolamine (PE) and ether-linked plasmalogen [1-alkenyl-2-acyl-glycerophosphoethanolamine (plasmenyl-PE)]. However, to date there has been no analysis of the metabolomic consequences of the mutation of EPT1 on the concentration of ethanolamine glycerophospholipids in mammalian cells. We studied a patient with severe complicated hereditary spastic paraplegia, sensorineural-deafness, blindness, and seizures. Neuroimaging revealed hypomyelination, followed by brain atrophy mainly in the cerebellum and brainstem. Using whole exome sequencing, we identified a novel EPT1 mutation (exon skipping). In vitro EPT activity, as well as the rate of biosynthesis of ethanolamine glycerophospholipids, was markedly reduced in cultures of the patient's skin fibroblasts. Quantification of phospholipids by LC-MS/MS demonstrated reduced levels of several PE species with polyunsaturated fatty acids, such as 38:6, 38:4, 40:6, 40:5, and 40:4. Notably, most plasmenyl-PE species were significantly decreased in the patient's cells, whereas most plasmanylcholine [1-alkyl-2-acyl-glycerophosphocholine (plasmanyl-PC)] species were increased. Similar findings regarding decreased plasmenyl-PE and increased plasmanyl-PC were obtained using EPT1-KO HeLa cells. Our data demonstrate for the first time the indispensable role of EPT1 in the myelination process and neurodevelopment, and in the maintenance of normal homeostasis of ether-linked phospholipids in humans.

Walker-Warburg syndrome and tectocerebellar dysraphia: A novel association caused by a homozygous DAG1 mutation.

OBJECTIVES: To elaborate the imaging phenotype associated with a homozygous c.743C > del frameshift mutation in DAG1 leading to complete absence of both α- and ß-dystroglycan previously reported in a consanguineous Israeli-Arab family. METHODS: We analyzed prenatal and postnatal imaging data of patients from a consanguineous Israeli-Arab kindred harboring the DAG1 mutation. RESULTS: The imaging studies (fetal ultrasound, CT scan and postnatal MRI) demonstrated: flat cortex (abnormally thick with irregular pebbled cortical-white matter border on MRI), hydrocephalus, scattered small periventricular heterotopia and subependymal hemorrhages and calcifications, z-shaped brainstem, and in addition an occipital encephalocele, vermian agenesis, and an elongated and thick tectum (tectocerebellar dysraphia). CONCLUSIONS: The novel association of cobblestone malformation with tectocerebellar dysraphia as part of WWS is characteristic of the homozygous c.743C > del frameshift mutation in the DAG1 gene.

Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy.

Leukoencephalopathies are a group of white matter disorders related to abnormal formation, maintenance, and turnover of myelin in the central nervous system. These disorders of the brain are categorized according to neuroradiological and pathophysiological criteria. Herein, we have identified a unique form of leukoencephalopathy in seven patients presenting at ages 2 to 4 months with progressive microcephaly, spastic quadriparesis, and global developmental delay. Clinical, metabolic, and imaging characterization of seven patients followed by homozygosity mapping and linkage analysis were performed. Next generation sequencing, bioinformatics, and segregation analyses followed, to determine a loss of function sequence variation in the phospholipase A2-activating protein encoding gene (PLAA). Expression and functional studies of the encoded protein were performed and included measurement of prostaglandin E2 and cytosolic phospholipase A2 activity in membrane fractions of fibroblasts derived from patients and healthy controls. Plaa-null mice were generated and prostaglandin E2 levels were measured in different tissues. The novel phenotype of our patients segregated with a homozygous loss-of-function sequence variant, causing the substitution of leucine at position 752 to phenylalanine, in PLAA, which causes disruption of the protein's ability to induce prostaglandin E2 and cytosolic phospholipase A2 synthesis in patients' fibroblasts. Plaa-null mice were perinatal lethal with reduced brain levels of prostaglandin E2 The non-functional phospholipase A2-activating protein and the associated neurological phenotype, reported herein for the first time, join other complex phospholipid defects that cause leukoencephalopathies in humans, emphasizing the importance of this axis in white matter development and maintenance.

A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis.

BACKGROUND: Members of two seemingly unrelated kindreds of Arab Moslem origin presented with pronounced early onset spastic paraparesis of upper and lower limbs, mild intellectual disability, kyphosis, pectus carinatum and hypertrichosis. METHODS: The authors performed neurological and developmental examinations on the affected individuals. The authors conducted whole genome linkage and haplotype analyses, followed by sequencing of candidate genes; RNA and protein expression studies; and finally proof of principle investigations on knockdown morpholino oligonucleotide injected zebrafish. RESULTS: The authors characterise a novel form of autosomal recessive complex hereditary spastic paraparesis (CHSP). MRI studies of brain and spinal cord were normal. Within a single significantly linked locus the authors ultimately identified a homozygous missense mutation c.1146A>T (p.K382N) in the vacuolar protein sorting 37A (Vps37A) gene, fully penetrant and segregating with the disease in both families. Mobility was significantly reduced in Vps37A knockdown morpholino oligonucleotide injected zebrafish, supporting the causal relationship between mutations in this gene and the phenotype described in the patients of this study. CONCLUSIONS: The authors provide evidence for the involvement of Vps37A, a member of the endosomal sorting complex required for transport (ESCRT) system, in upper motor neuron disease. The ESCRT system has been shown to play a central role in intracellular trafficking, in the maturation of multivesicular bodies and the sorting of ubiquitinated membrane proteins into internal luminal vesicles. Further investigation of mechanisms by which dysfunction of this gene causes CHSP will contribute to the understanding of intracellular trafficking of vesicles by the ESCRT machinery and its relevance to CHSP.

Epilepsia partialis continua associated with widespread gliomatosis cerebri.

We report an uncommon association of intractable epilepsia partialis continua that was the main presentation of widespread gliomatosis cerebri in two females. Both children had a preceding prolonged secondary generalized seizure 2-4 months before the evolution of epilepsia partialis continua, including recurrent clusters of left-sided myoclonic twitching and sensory impairment. During these events, the children remained fully alert. These seizures were corroborated by prolonged focal epileptic spike/wave discharges evident on the electroencephalograms. Cerebral magnetic resonance imaging in the first patient demonstrated a wide area of increasing signals over the right frontocentral regions, along with diffuse cortical-subcortical infiltration impinging on the left hemisphere. In the second patient a cortical lesion was suspected. Evaluation for Rasmussen's encephalitis, focal cortical dysplasia, or a gliomatous process was conducted; the patients underwent a stereotactic brain biopsy in which the histologic findings were compatible with gliomatosis cerebri with diffuse widespread infiltration of glioma cells with no constitution of a circumscribed tumor mass. The first patient was treated with cranial radiation, chemotherapy, steroids, and combined antiepileptic therapy. The focal seizures gradually but markedly decreased in frequency, and sensory impairment abated within 18 months after establishment of the diagnosis and ensuing therapy. Cognition remains intact. The second female died 2 years after presentation despite massive chemotherapy and antiepileptic medications. Although rare, gliomatosis cerebri should be taken into account in the differential diagnosis of epilepsia partialis continua in children to facilitate a rapid diagnosis and initiation of prompt treatment of this rare disorder that may respond to a concurrent effective combination of cranial radiation, chemotherapy, and antiepileptic medications.

Valproic acid therapy inducing absence status evolving into generalized seizures.

The authors herein present two children with mild absence epilepsy, having intermittent absences, who developed absence status evolving into atonic generalized seizures and drop attacks along with progressive disorientation induced by relatively small doses of valproic acid. Consciousness and awareness were intact before the introduction of valproic acid. Both children, after the first dose of valproic acid, developed prolonged and recurrent clusters of absences, which became prolonged, with drop attacks occurring in one patient associated with progressive disorientation. The electroencephalogram concurrently demonstrated prolonged spike-wave discharges, along with disturbance of background activity. Discontinuation of valproic acid resulted in immediate cessation of the prolonged and repetitive clusters of absence episodes and disappearance of drop attacks, along with sensorium clearing. In conclusion, although uncommon, a possible induction of absence status and even atonic seizures by valproic acid should be taken into account and properly managed by abrupt discontinuation of the drug.

Outcome of severe encephalomyelitis in children: effect of high-dose methylprednisolone and immunoglobulins.

Acute encephalomyelitis in children refers to an insult of cortical white matter leading to acute disseminated encephalomyelitis, insult of the spinal cord leading to multifocal myelopathy, or a combined form of encephalomyelitis. We report here the clinical presentations and outcome of 16 children with severe acute encephalomyelitis analyzing the effect of high-dose methylprednisolone or intravenous immunoglobulins, administered separately or in combination. Five children developed acute disseminated encephalomyelitis alone, eight developed severe multifocal myelopathy accompanied in two of them by radiculoneuropathy, and three developed the most severe form of combined encephalomyeloradiculoneuropathy. The indications for treatment with either high-dose methylprednisolone, intravenous immunoglobulin, or a combination of the two were severe acute disseminated encephalomyelitis, visual loss, or severe flaccid weakness accompanied by bladder and bowel incontinence. Overall, 10 children had remarkably responded to high-dose methylprednisolone alone and recovered within 10 days. One patient with severe myelopath, developing paraplegia, who failed oral corticosteroids completely recovered following intravenous immunoglobulin. Of the isolated acute disseminated encephalomyelitis group, all patients were initially treated with high-dose intravenous methylprednisolone and recovered within 10 days, including visual remission in the child with severe optic neuritis. All six children with solitary severe multifocal myelopathy were treated with high-dose methylprednisolone alone and recovered within the first week. Two patients had severe myeloradiculoneuropathy and were therefore treated with combined high-dose methylprednisolone and intravenous immunoglobulin: one remains paraplegic, whereas the second was ventilated for 3 weeks and recovered after 2 months. The three children with the most severe form of encephalomyeloradiculoneuropathy were treated with combined high-dose methylprednisolone and intravenous immununoglobulin; two remain severely handicapped, of whom one is paraplegic, and the third unexpectedly recovered within 3 months. Therefore, our experience indicates that either high-dose methylprednisolone or intravenous immunoglobulin, given separately or combined, may be efficacious in severe debilitating pediatric-onset acute encephalomyelitis. In children with the most severe form of encephalomyeloradiculoneuropathy, we suggest initially administering high-dose methylprednisolone and intravenous immunoglobulin combined, given the poorer outcome of our patients with combined severe central and peripheral demyelination.