Cerebral Palsy

Uniparental disomy (UPD) for chromosome 14 is associated with well-recognized phenotypes, depending on the parent of origin. Studies in mouse models and human patients have implicated the involvement of the distal region of the long arm of chromosome 14 in the distinctive phenotypes. This involvement is supported by the identification of an imprinting cluster at chromosome 14q32, encompassing the differentially methylated regions (DMRs), IG-DMR and MEG3-DMR, as well as the maternally expressed genes GTL2, DIO3, and RTL1 and the paternally expressed genes DLK1, RTL1as, and MEG8. Here we report on a preterm female infant with distal segmental paternal UPD14 (upd(14)pat) of 14q32-14q32.33, which resulted in thoracic deformity secondary to rib abnormalities (“coat-hanger” rib sign), polyhydramnios, and other congenital abnormalities characteristically described in cases of complete upd(14)pat. Microsatellite investigation demonstrated UPD of markers D14S250 and D14S1010, encompassing a approximately 3.5 Mb region of distal 14q and involving the imprinting cluster. This case provided insight into the etiology of the phenotypic effects of upd(14)pat, prompting methylation analysis of the GTL2 promoter and the DMR between GTL2 and DLK1. We compare the physical findings seen in this case with those of patients with other causes of abnormal methylation of 14q32, which consistently result in certain distinct clinical features, regardless of the cytogenetic and molecular etiology. (c) 2010 Wiley-Liss, Inc.

X-linked cerebral creatine deficiency is caused by the deficiency of the creatine transporter encoded by the SLC6A8 gene. Here, we report two half-brothers with this condition and characterize creatine transport in human fibroblasts. The propositus presented at 6 months of age with delays in development and slow progress since then with no regression. Seizures started at 3.5 years of age and responded well to treatment with anticonvulsants. He had failure to thrive with all growth parameters (including head size) at or below the fifth centile. Brain MRI indicated hemispheric white matter abnormalities, while MR spectroscopy indicated markedly reduced creatine peak. Biochemical testing indicated increased urine creatine/creatinine ratio, with normal plasma creatine and guanidinoacetate. To confirm the diagnosis, we measured ([14])C-creatine transport in fibroblasts. ([14])C-Creatine transport in normal human fibroblasts was linear for up to 2 hr at 37 degrees C. Kinetic studies indicated the presence of a single saturable creatine transporter with a K(m) of 34.7 +/- 2.5 microM. Fibroblasts from the propositus lacked creatine transport. DNA testing indicated hemizygosity for a novel deletion producing a frameshift (c.974_975delCA, p.Thr325SerfsX139) in the creatine transporter gene. His 12-year-old half-brother had similar biochemical and clinical abnormalities except for the presence of macrocephaly and the absence of seizures. The mother had history of seizures in childhood, but had normal development. These results show that human fibroblasts have a single major creatine transporter and that measurement of its specific activity can confirm creatine transporter deficiency. (c) 2010 Wiley-Liss, Inc.

Café-au-lait macules are frequently seen in Ras-MAPK pathway disorders and are a cardinal feature of neurofibromatosis type 1 (NF1). Most NF1 individuals develop age-related tumorigenic manifestations (e.g., neurofibromas), although individuals with a specific 3-bp deletion in exon 22 of NF1 (c.2970_2972delAAT) have an attenuated phenotype with primarily pigmentary manifestations. Previous reports identify this deletion c.2970_2972delAAT in exon 17 of NF1 using NF Consortium nomenclature. For this report, we elected to use standard NCBI nomenclature, which places this identical deletion within exon 22. SPRED1 mutations cause Legius syndrome, which clinically overlaps with this attenuated NF1 phenotype. In an unselected cohort of 50 individuals who fulfilled NIH clinical diagnostic criteria from an NF Clinic and did not have SPRED1 mutations, we sequenced NF1 exon 22 in order to identify children and adolescents with multiple café-au-lait spots who could be projected to have lower likelihood to develop tumors. Two individuals with NF1 exon 22 mutations were identified: an 11-year-old boy with the c.2970_2972delAAT in-frame deletion and a 4-year-old boy with c.2866dupA. The father of the second patient had an attenuated form of NF1 and showed 24% germline mosaicism of the c.2866dupA mutation in whole blood. These individuals emphasize the need for mutation analysis in some individuals with the clinical diagnosis of NF1 who lack the tumorigenic or classic skeletal abnormalities of NF1. Specifically, with the identification of Legius syndrome, the need to recognize the attenuated phenotype of NF1 mosaicism and confirmation by mutation analysis is increasingly important for appropriate medical management and family counseling. (c) 2010 Wiley-Liss, Inc.

Dates of special, historical significance, such as the 50th anniversary of the founding of the Teratology Society, prompt a desire to pause and look back and contemplate where we began, how far we have come, and consider the future for our scientific endeavors. The study of the etiology of cleft palate extends many years into the past and was a subject of interest to many of the founding members of the Teratology Society. This research area was intensively pursued and spawned a vast portfolio of published research. This article will look back at the state of the science around the time of the founding of the Teratology Society, in the 1950s and 1960s, and track the emergence and pursuit of an interest in an etiology for cleft palate involving failure of palatal fusion. Studies of medial epithelial cell fate and induction of cleft palate by interference with adhesion or fusion span the period from the 1960s to the present time. Teratology Society members have been and continue to be key players in cleft palate research. In this retrospective article, seminal research published by Teratology Society members will serve as a platform to launch the discussion of the emergence of our current understanding of medial epithelial cell differentiation and fate and the potential for these processes to be targets of teratogenic action. Birth Defects Res (Part B) XX:1-9, 2010. Published 2010 Wiley-Liss, Inc.

PURPOSE: Data linkage of population administrative data is being investigated as a tool for pharmacovigilance in pregnancy in Australia. Records of prescriptions of known or suspected teratogens dispensed to pregnant women have been linked to a birth defects registry to determine if defects associated with medicine exposure can be detected. METHODS: The Pharmaceutical Benefits Scheme is a national claims database that has been linked with population-based data to extract linkages for women with a pregnancy event in Western Australia from 2002 to 2005 (n = 106 074). Records of births to the women who were dispensed medicines in categories D or X of the Australian ADEC pregnancy risk category were linked to the Birth Defects Registry of Western Australia. Population rates of registered birth defects per 1000 births were calculated for each medicine. RESULTS: There were 47 medicines dispensed at least once during pregnancy with 23 associated with a registered birth defect to a woman dispensed the medicine. When the birth defect rate for each medicine was compared with the rate for all other women not dispensed that medicine, most medicines showed an increased risk. Medicines with the higher risks were medroxyprogesterone acetate (OR: 1.8; 95%CI: 1.4-2.3), follitropin alfa (OR: 2.5; 95%CI: 1.2-5.0), carbamazepine (OR: 3.1; 95%CI: 1.7-5.6) and enalapril maleate (OR: 8.1; 95%CI: 1.6-41.7). CONCLUSION: Many known associations between medicines and birth defects were identified, suggesting that linked administrative data could be an important means of pharmacovigilance in pregnancy in Australia. Copyright (c) 2010 John Wiley & Sons, Ltd.

Isolated spinal cord injuries can rarely be found in patients with no traumatic radiological abnormalities of the spine. Stenoses of the medullary canal and degeneration of cervical spine are the predisposing factors. A case report of a 68-year-old patient is described, who developed quadriplegia with cardiac arrest due to isolated cervical spinal cord injury while jumping on a trampoline. Compressions of the spinal cord with intramedullary and epidural haemorrhage between vertebrae C3 and C6 were observed with no traumatic radiological abnormalities of the spine skeleton.

Degeneration of motor neurons contributes to senescence-associated loss of muscle function and underlies human neurodegenerative conditions such as amyotrophic lateral sclerosis and spinal muscular atrophy. The identification of genetic factors contributing to motor neuron vulnerability and degenerative phenotypes in vivo are therefore important for our understanding of the neuromuscular system in health and disease. Here, we analyzed neurodegenerative abnormalities in the spinal cord of progeroid Ercc1 ( Delta/-) mice that are impaired in several DNA repair systems, i.e. nucleotide excision repair, interstrand crosslink repair, and double strand break repair. Ercc1 ( Delta/-) mice develop age-dependent motor abnormalities, and have a shortened life span of 6-7 months. Pathologically, Ercc1 ( Delta/-) mice develop widespread astrocytosis and microgliosis, and motor neuron loss and denervation of skeletal muscle fibers. Degenerating motor neurons in many occasions expressed genotoxic-responsive transcription factors p53 or ATF3, and in addition, displayed a range of Golgi apparatus abnormalities. Furthermore, Ercc1 ( Delta/-) motor neurons developed perikaryal and axonal intermediate filament abnormalities reminiscent of cytoskeletal pathology observed in aging spinal cord. Our findings support the notion that accumulation of DNA damage and genotoxic stress may contribute to neuronal aging and motor neuron vulnerability in human neuromuscular disorders.

Septo-optic dysplasia (SOD), also referred to as de Morsier syndrome, is a rare congenital condition, characterized by two of the classic triad features: midline brain abnormalities, optic nerve hypoplasia (ONH) and pituitary endocrine dysfunction. We report 5 children with SOD, originally referred to be evaluated due to short stature, who also presented bilateral optic nerve hypoplasia, nystagmus and development delay. In 4 of the patients, we identified neuroimaging abnormalities of the hypothalamo-pituitary axis such as anterior pituitary hypoplasia (3/5), ectopic posterior pituitary (4/5), thin or absent stalk (3/5) and empty sella (1/5). We also encountered diverse pituitary deficiencies: growth hormone (3/5), adrenocorticotropic hormone (3/5), thyroid-stimulating hormone (2/5) and antidiuretic hormone (1/5). Only one child presented intact pituitary function and anatomy. Although rare, SOD is an important cause of congenital hypopituitarism and it should be considered in children with optic nerve hypoplasia or midline brain abnormalities for early diagnosis and treatment.

OBJECTIVE: To identify in mild head injured children the major differences between those with a Glasgow Coma Scale (GCS) 15 and GCS 13/14. METHOD: Cross-sectional study accomplished through information derived from medical records of mild head injured children presented in the emergency room of a Pediatric Trauma Centre level I, between May 2007 and May 2008. RESULTS: 1888 patients were included. The mean age was 7.6+/-5.4 years; 93.7% had GCS 15; among children with GCS 13/14, 46.2% (p<0.001) suffered multiple traumas and 52.1% (p<0.001) had abnormal cranial computed tomography (CCT) scan. In those with GCS 13/14, neurosurgery was performed in 6.7% and 9.2% (p=0.001) had neurological disabilities. CONCLUSION: Those with GCS 13/14 had frequently association with multiple traumas, abnormalities in CCT scan, require of neurosurgical procedure and Intensive Care Unit admission. We must be cautious in classified children with GCS 13/14 as mild head trauma victims.

BACKGROUND: Detection of hypertensive retinopathy (HR) with direct ophthalmoscopy is part of the assessment of hypertensive patients. Its use has been questioned because of its subjectivity and high interobserver variability. OBJECTIVE: To determine the prevalence of HR in hypertensive patients under outpatient monitoring, the correlation between diagnosis and ophthalmoscopy and angiography, and to correlate it with other target organ damages. METHODS: An observational, analytical and cross-sectional evaluation of 99 patients. Direct ophthalmoscopy and angiography performed by two investigators independently. Classification of RH, as described by Keith, Wagener and Barker. RESULTS: The prevalence of HR of any grade was higher than 90.0% by both methods. On ophthalmoscopy, we observed grade I abnormalities in 51.0%, grade II in 43.0%, with one patient with grade III HR. On angiography, we observed grade I abnormalities in 42.0% and grade II in 52.0%. We detected three patients with grade III HR, two of which were not detected by ophthalmoscopy. Observers’ agreement for the presence and severity of HR was poor with direct ophthalmoscopy and good with angiography. Renal dysfunction, ECG abnormalities (ventricular hypertrophy, pathological Q wave, repolarization abnormalities), and history of stroke were observed in 70.0%, 27.0% and 10.0% of patients, respectively. There was no relationship between the severity of HR and other target organ damages. CONCLUSION: We observed a high prevalence of HR using both methods. Observers’ agreement for the diagnosis and determination of the severity of HR was better with angiography. In our sample, there was no association of the severity of HR with other target organ damages.