Cerebral Palsy Research Group publications
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Item Metadata only Cerebral palsy – genomic susceptibility and environmental triggers(Wiley, 2009) MacLennan, A.; International Cerebral Palsy Conference (3rd : 2009 : Sydney, New South Wales); Robinson InstituteItem Metadata only Apolipoprotein E genotype is not associated with cerebral palsy(Wiley, 2009) McMichael, G.; Gibson, C.; MacLennan, A.; Goldwater, P.; Haan, E.; Priest, K.; Dekker, G.; International Cerebral Palsy Conference (3rd : 2009 : Sydney, New South Wales); Robinson InstituteItem Metadata only Genetic and environmental risk factors that contribute to cerebral palsy(Wiley, 2010) McMichael, G.; Gibson, C.; Goldwater, P.; Haan, E.; Priest, K.; O’Callaghan, M.; MacLennan, A.; Biennial Conference of the Australasian Academy of Cerebral Palsy & Developmental Medicine (5th : 2010 : Christchurch, New Zealand); Robinson InstituteItem Metadata only Cerebral palsy – Is it in your genes? Genetic susceptibility and environmental risk factors(Wiley, 2012) MacLennan, A.; Biennial Conference of the Australasian Academy of Cerebral Palsy & Developmental Medicine (6th : 2012 : Brisbane, Australia); Robinson InstituteItem Open Access NKX2-1 mutation in a family diagnosed with ataxic dyskinetic cerebral palsy(Editions Scientifiques Medicales Elsevier, 2013) McMichael, G.; Haan, E.; Gardner, A.; Yap, T.; Thompson, S.; Ouvrier, R.; Dale, R.; Gecz, J.; MacLennan, A.; Robinson InstituteBenign hereditary chorea caused by mutations in the NK2 homeobox 1 gene (NKX2-1), shares clinical features with ataxic and dyskinetic cerebral palsy (CP), resulting in the possibility of misdiagnosis. A father and his two children were considered to have ataxic CP until a possible diagnosis of benign familial chorea was made in the children in early teenage. The father's neurological condition had not been appreciated prior to examination of the affected son. Whole exome sequencing of blood derived DNA and bioinformatics analysis were performed. A 7 bp deletion in exon 1 of NKX2-1, resulting in a frame shift and creation of a premature termination codon, was identified in all affected individuals. Screening of 60 unrelated individuals with a diagnosis of dyskinetic or ataxic CP did not identify NKX2-1 mutations. BHC can be confused with ataxic and dyskinetic CP. Occasionally these children have a mutation in NKX2-1.Item Metadata only Cesarean delivery and cerebral palsy: A systematic review and meta-analysis(Lippincott Williams & Wilkins, 2013) O'Callaghan, M.; MacLennan, A.; Robinson InstituteOBJECTIVE: To examine the association of cesarean delivery and cerebral palsy using a systematic literature review and meta-analysis. DATA SOURCES: MEDLINE, Embase, and ClinicalTrials. gov were systematically searched for articles relating to cerebral palsy and cesarean delivery from inception until December 2012. Only articles reporting confirmed cases of cerebral palsy were included. Meta-analysis was used to assess combined results and also the following subgroups: emergency cesarean; elective cesarean; term delivery; preterm delivery; and delivery of breech-presenting newborns. METHODS OF STUDY SELECTION: Literature searches returned 1,874 articles with 58 considered in full. Studies were selected if they reported an endpoint of cerebral palsy, an intervention or risk of cesarean delivery, were in English, and gave sufficient details to perform meta-analysis. TABULATION, INTEGRATION, AND RESULTS: Nine case–control and four cohort studies were included in the overall analysis. Meta-analysis showed no overall association of cesarean delivery with cerebral palsy (odds ratio [OR] 1.29; 95% confidence interval [CI] 0.92–1.79; 3,810 case group participants and 1,692,580 control group participants). Emergency cesarean delivery was associated with increased risk of cerebral palsy (OR 2.17; 95% CI 1.58–2.98), whereas there was no significant association between elective cesarean delivery and cerebral palsy (OR 0.81; 95% CI 0.41–1.58). Any type of cesarean delivery (elective or emergency) for term newborns was associated with cerebral palsy (OR 1.6; 95% CI 1.05–2.44), whereas there was no association between any type of cesarean delivery and cerebral palsy in preterm newborns (OR 0.81; 95% CI 0.47–1.40). Cesarean delivery did not significantly modify cerebral palsy risk for breech-presenting newborns (OR 0.51; 95% CI 0.13–2.05).Item Open Access Rare copy number variation in cerebral palsy(Nature Publishing Group, 2013) McMichael, G.; Girirajan, S.; Moreno-De-Luca, A.; Gecz, J.; Shard, C.; Nguyen, L.; Nicholl, J.; Gibson, C.; Haan, E.; Eichler, E.; Martin, C.; MacLennan, A.Recent studies have established the role of rare copy number variants (CNVs) in several neurological disorders but the contribution of rare CNVs to cerebral palsy (CP) is not known. Fifty Caucasian families having children with CP were studied using two microarray designs. Potentially pathogenic, rare (<1% population frequency) CNVs were identified, and their frequency determined, by comparing the CNVs found in cases with 8329 adult controls with no known neurological disorders. Ten of the 50 cases (20%) had rare CNVs of potential relevance to CP; there were a total of 14 CNVs, which were observed in <0.1% (<8/8329) of the control population. Eight inherited from an unaffected mother: a 751-kb deletion including FSCB, a 1.5-Mb duplication of 7q21.13, a 534-kb duplication of 15q11.2, a 446-kb duplication including CTNND2, a 219-kb duplication including MCPH1, a 169-kb duplication of 22q13.33, a 64-kb duplication of MC2R, and a 135-bp exonic deletion of SLC06A1. Three inherited from an unaffected father: a 386-kb deletion of 12p12.2-p12.1, a 234-kb duplication of 10q26.13, and a 4-kb exonic deletion of COPS3. The inheritance was unknown for three CNVs: a 157-bp exonic deletion of ACOX1, a 693-kb duplication of 17q25.3, and a 265-kb duplication of DAAM1. This is the first systematic study of CNVs in CP, and although it did not identify de novo mutations, has shown inherited, rare CNVs involving potentially pathogenic genes and pathways requiring further investigation.Item Open Access Single-nucleotide polymorphism associations with preterm delivery: a case-control replication study and meta-analysis(Int Pediatric Research Foundation Inc, 2013) O'Callaghan, M.; MacLennan, A.; McMichael, G.; Haan, E.; Dekker, G.Background
The aim of this study was to replicate single-nucleotide polymorphism (SNP) associations with preterm birth (PTB; birth at <37 completed weeks of gestation) and synthesize currently available evidence using meta-analysis.Methods
Spontaneous PTB cases and controls were selected from an existing cohort. Candidate SNPs were taken from an existing genotype panel. A systematic review was conducted for each SNP in the panel to determine suitability as a PTB candidate. Those with significant associations previously reported in Caucasians were selected for replication. Candidate SNPs were already genotyped in cases and controls and clinical data were accessed from state perinatal and cerebral palsy databases. Association analysis was conducted between each SNP and PTB, and meta-analysis was conducted if there were ≥ 3 studies in the literature. Maternal and fetal SNPs were considered as separate candidates.Results
A cohort of 170 cases and 583 controls was formed. Eight SNPs from the original panel of genotyped SNPs were selected as PTB candidates and for replication on the basis of systematic literature review results. In our cohort, fetal factor V Leiden (FVL) was significantly associated with PTB (odds ratio (OR): 2.6, 95% confidence interval (CI): 1.31-5.17), and meta-analysis confirmed this association (OR: 2.71, 95% CI: 1.15-6.4).Conclusion
Replication and meta-analysis support an increased risk of PTB in Caucasians with the fetal FVL mutation.Item Open Access Genetic and clinical contributions to cerebral palsy: A multi-variable analysis(Blackwell Publishing Asia, 2013) O'Callaghan, M.; MacLennan, A.; Gibson, C.; McMichael, G.; Haan, E.; Broadbent, J.; Baghurst, P.; Goldwater, P.; Dekker, G.Aim
This study aims to examine single nucleotide polymorphism (SNP) associations with cerebral palsy in a multi-variable analysis adjusting for potential clinical confounders and to assess SNP-SNP and SNP-maternal infection interactions as contributors to cerebral palsy.Methods
A case control study including 587 children with cerebral palsy and 1154 control children without cerebral palsy. Thirty-nine candidate SNPs were genotyped in both mother and child. Data linkage to perinatal notes and cerebral palsy registers was performed with a supplementary maternal pregnancy questionnaire. History of known maternal infection during pregnancy was extracted from perinatal databases.Results
Both maternal and fetal carriage of inducible nitric oxide synthase SNP rs1137933 were significantly negatively associated with cerebral palsy in infants born at less than 32 weeks gestation after adjustment for potential clinical confounders and correction for multiple testing (odds ratio 0.55, 95% confidence interval 0.38-0.79; odds ratio 0.57, 95% confidence interval 0.4-0.82, respectively). Analysis did not show any statistically significant SNP-SNP or SNP-maternal infection interactions after correction for multiple testing.Conclusions
Maternal and child inducible nitric oxide synthase SNPs are associated with reduced risk of cerebral palsy in infants born very preterm. There was no evidence for statistically significant SNP-SNP or SNP-maternal infection interactions as modulators of cerebral palsy risk.Item Metadata only Apolipoprotein E and the genetics of cerebral palsy - where to next?(Cambridge Univ Press, 2013) O'Callaghan, M.This commentary is on the original article by Lien et al on pages 372–377of this issue.Item Metadata only ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity(Univ Chicago Press, 2013) Hirata, H.; McMichael, G.; Haan, E.; MacLennan, A.; Yap, T.; Nguyen, L.; Shaw, M.; Gecz, J.Arthrogryposis multiplex congenita (AMC) is caused by heterogeneous pathologies leading to multiple antenatal joint contractures through fetal akinesia. Understanding the pathophysiology of this disorder is important for clinical care of the affected individuals and genetic counseling of the families. We thus aimed to establish the genetic basis of an AMC subtype that is associated with multiple dysmorphic features and intellectual disability (ID). We used haplotype analysis, next-generation sequencing, array comparative genomic hybridization, and chromosome breakpoint mapping to identify the pathogenic mutations in families and simplex cases. Suspected disease variants were verified by cosegregation analysis. We identified disease-causing mutations in the zinc-finger gene ZC4H2 in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy. Several heterozygous females were also affected, but to a lesser degree. Furthermore, we found two ZC4H2 deletions and one rearrangement in two female and one male unrelated simplex cases, respectively. In mouse primary hippocampal neurons, transiently produced ZC4H2 localized to the postsynaptic compartment of excitatory synapses, and the altered protein influenced dendritic spine density. In zebrafish, antisense-morpholino-mediated zc4h2 knockdown caused abnormal swimming and impaired α-motoneuron development. All missense mutations identified herein failed to rescue the swimming defect of zebrafish morphants. We conclude that ZC4H2 point mutations, rearrangements, and small deletions cause a clinically variable broad-spectrum neurodevelopmental disorder of the central and peripheral nervous systems in both familial and simplex cases of both sexes. Our results highlight the importance of ZC4H2 for genetic testing of individuals presenting with ID plus muscle weakness and minor or major forms of AMC.Item Open Access Brain damage and maternal medication(Mosby Inc, 2013) O'Callaghan, M.; MacLennan, A.Item Metadata only Cytomegalovirus and Epstein–Barr virus may be associated with some cases of cerebral palsy(Taylor & Francis Ltd, 2012) McMichael, G.; MacLennan, A.; Gibson, C.; Alvino, E.; Goldwater, P.; Haan, E.; Dekker, G.Objective: Intrauterine infection is a risk factor for cerebral palsy. Previous work reported a high frequency of viral DNA in newborn screening cards from cerebral palsy cases and controls possibly due to contamination. Methods: Retrospective case-control study using improved methodologies to minimize contamination during PCR-based detection of viral DNA sequences. Newborn screening cards of 339 Caucasian children with cerebral palsy and 594 controls were examined. Viruses tested were herpes simplex viruses 1 and 2 (HSV1 and 2), varicella zoster virus (VZV), Epstein–Barr virus (EBV), cytomegalovirus (CMV), human herpes viruses 6, 7 and 8 (HHV6, HHV7 and HHV8), and parvovirus B19. Genotyping was performed on DNA extracted from dried blood spots. Results: CMV and EBV were detected in 5 (1.5%) and 3 (0.9%) of 339 cases, respectively, but not in controls (p = 0.047 and 0.006). Frequencies of detection of the other viruses examined were similar for cases and controls. DNA from at least one of the nine viruses tested was found in 4.4% of cases and 3.1% of controls [OR 1.4 95% CI (0.71–2.76)]. Conclusion: Evidence of congenital viral infection was uncommon in cases of cerebral palsy and controls. However, CMV and EBV were significantly associated with cerebral palsy.Item Metadata only Risk management in cerebral palsy(RANZCOG, 2000) MacLennan, A.A protocol to reduce inappropriate recrimination if cerebral palsy ensues when perinatal asphyxia is suspected after birthItem Metadata only Fetal and maternal candidate single nucleotide polymorphism associations with Cerebral Palsy: a case-control study(Amer Acad Pediatrics, 2012) O'Callaghan, M.; MacLennan, A.; Gibson, C.; McMichael, G.; Haan, E.; Broadbent, J.; Goldwater, P.; Painter, J.; Montgomery, G.; Dekker, G.; Australian Collaborative Cerebral Palsy Research GroupObjective
Previous studies have suggested associations between certain genetic variants and susceptibility to cerebral palsy (CP). This study was designed to assess established and novel maternal and child genetic and epidemiologic risk factors for CP along with their interactions.Methods
DNA from 587 case and 1154 control mother-child pairs was analyzed. A panel of 35 candidate single nucleotide polymorphisms (SNPs) were examined and included SNPs in genes associated with (1) thrombophilia, (2) inflammation, and (3) risk factors for CP (eg, preterm birth). Comparisons were specified a priori and made by using a χ(2) test.Results
There were 40 fetal and 28 maternal associations with CP when analyzed by CP subtype, gestational age, genotypes of apolipoprotein E, and haplotypes of mannose-binding-lectin. After Bonferroni correction for multiple testing, no fetal or maternal candidate SNP was associated with CP or its subtypes. Only fetal carriage of prothrombin gene mutation remained marginally associated with hemiplegia in term infants born to mothers with a reported infection during pregnancy. Odds ratio directions of fetal SNP associations were compared with previously reported studies and confirmed no trend toward association.Conclusions
Except for the prothrombin gene mutation, individual maternal and fetal SNPs in our candidate panel were not found to be associated with CP outcome. Past reported SNP associations with CP were not confirmed, possibly reflecting type I error from small numbers and multiple testing in the original reports.Item Metadata only A 'no-fault' cerebral palsy pension scheme would benefit all Australians(Blackwell Publishing Asia, 2011) MacLennan, A.The Australian Federal Productivity Commission is proposing two new schemes to better support those with major disability. The main National Disability Insurance Scheme (NDIS) will provide long-term care and support for the disabled. A smaller scheme, the National Injury Insurance Scheme (NIIS), will provide ‘no-fault ‘support for those following an accident or ‘medical injury’. It is proposed that cerebral palsy (CP) is part of the NIIS. While this brings quicker and more equitable benefits to CP families, the scheme labels CP as a ‘medical accident’ and infers preventability. Obstetricians will fund much of the system. Despite being labelled a ‘no-fault’ system, maternity staff can still be litigated for extensive ‘head of damages’, eg loss of earning capacity. An additional option is for federal/state legislation to introduce a true ‘no-fault’ lifetime pension specifically for all children on CP registers. This pension would be graded by degree of disability and dependent on waiving civil litigation. Savings in medico-legal costs and potentially a 7% reduction in caesarean delivery would cover the estimated annual cost of $50 000 per annum indexed life pension for severe CP cases and the total annual cost of AUD $93 million for Australia. This pension and the NDIS would help cover the needs of children with CP without recourse to prolonged litigation and without detriment to the maternity services of Australia, caused by defensive obstetrics and maternity hospital closure because of CP litigation.Item Metadata only Epidemiologic associations with cerebral palsy(Lippincott Williams & Wilkins, 2011) O'Callaghan, M.; MacLennan, A.; Gibson, C.; McMichael, G.; Haan, E.; Broadbent, J.; Goldwater, P.; Dekker, G.Objective
To estimate epidemiologic risk factors for cerebral palsy.Methods
Data were collected by linkage to state-based perinatal repositories and cerebral palsy registers and using a maternal questionnaire. The cohort included 587 individuals with cerebral palsy and 1,154 non-cerebral palsy controls.Results
The following factors were associated with cerebral palsy: recorded maternal infection during pregnancy (41.4% patients compared with 31.3% controls; odds ratio [OR] 1.55, 95% confidence interval 1.26-1.91), small for gestational age ([birth weight less than third customized centile] 43.9% patients compared with 6.3% controls; OR 11.75, 6.25-22.08), gestational age less than 32 weeks (29.3% patients compared with 0.7% controls; OR 59.20, 28.87-121.38), multiple birth (OR 6.62, 4.00-10.95), a relative with cerebral palsy (OR 1.61, 1.12-2.32), breech position (13.7% patients compared with 6.0% controls; OR 2.48, 1.76-3.49), bleeding at any time in pregnancy (29.3% patients compared with 16.9% controls; OR 2.04, 1.61-2.58), male sex (58.8% patients compared with 45.8% controls; OR 1.68, 1.38-2.06), multiple miscarriage (7.7% patients compared with 3.5% controls; OR 2.30, 1.38-3.82), smoking (14.0% patients compared with 10.6% controls; OR 1.37, 1.02-1.85), and illicit drug use (3.3% patients compared with 1.5% controls; OR 2.22, 1.14-4.30). Factors not associated with cerebral palsy were "disappearing twin," diabetes, maternal body mass index, hypertension, alcohol consumption, anemia, maternal hypothyroidism, forceps or vacuum delivery, and maternal age.Conclusion
Preterm birth, intrauterine growth restriction, perinatal infection, and multiple birth present the largest risks for a cerebral palsy outcome. Reassuringly, upper respiratory tract and gastrointestinal infections during pregnancy were not associated with cerebral palsy.Level of evidence
II.Item Metadata only Gathering the evidence: Cord gases and placental histology for births with low Apgar scores(Blackwell Publishing Asia, 2011) Wong, L.; MacLennan, A.Background: Acute intrapartum hypoxia is an uncommon cause of cerebral palsy. The exclusion of acute intrapartum hypoxia utilizes two vital pieces of information that can be obtained at the time of birth: (i) cord blood gas to exclude a severe metabolic acidosis, and (ii) placental histology to suggest an alternative aetiology other than acute intrapartum hypoxia. Although recommendations exist to encourage this practice in high-risk deliveries, their compliance in an Australian setting is not known. Aims: To evaluate the frequency and utility of cord blood gases and placental histology following delivery with an Apgar score ≤6 at five minutes. Methods: A retrospective study of 12,887 consecutive deliveries at a tertiary obstetric centre, of which 100 live births had Apgar scores ≤6 at five minutes. Cord blood gases and placental histology were examined. There were also 132 stillbirths where placental histology was sought. Results: Cord gases were measured in 52 of 100 live births with a low Apgar score. Seven of these had severe metabolic acidaemia and 26 had normal cord gases. Placental histology was requested in 40 of these births and 30 showed abnormal histology, suggesting alternative aetiologies. Of the 132 stillbirths, placental histology was available in 50. Abnormal histology was present in 39 of these stillbirths. Conclusions: Cord gases and placental histology should be sought in all babies with low Apgar scores for the benefit of understanding causation, counselling of the parents, research and professional liability assessment. Heightened awareness for adverse perinatal outcomes is required by health care professionals when a neonate requires resuscitation.Item Metadata only The Australian cerebral palsy research study - Protocol for a national collaborative study investigating genomic and clinical associations with cerebral palsy(Blackwell Publishing Asia, 2011) O'Callaghan, M.; MacLennan, A.; Gibson, C.; McMichael, G.; Haan, E.; Broadbent, J.; Priest, K.; Goldwater, P.; Dekker, G.Aim: Previous studies have proposed a link between the presence of specific single nucleotide polymorphisms (SNPs) and cerebral palsy and the majority of these associations remain to be confirmed or rejected by prospective studies with sufficient statistical power. Prior studies have also given little attention to the interaction of genomic characteristics and clinical risk factors. Methods: This paper describes the design of a prospective case-control study to test these genetic associations in conjunction with more stringent data collection in respect to clinical features associated with pregnancy, particularly maternal infection. Here we consider the ethical requirements, our hypothesis that genetic susceptibility modifies the risk of cerebral palsy in the presence of perinatal environmental triggers, a priori primary and secondary aims, power calculations, participant recruitment strategies, data linkage, sampling methods of genetic material and subsequent SNP analysis, collection of clinical data and the proposed final statistical analysis.Item Metadata only Comparison of DNA extraction methods from small samples of newborn screening cards suitable for retrospective perinatal viral research(The Association of Biomolecular Resource Facilities, 2011) McMichael, G.; Highet, A.; Gibson, C.; Goldwater, P.; O'Callaghan, M.; Alvino, E.; MacLennan, A.; South Australian Cerebral Palsy Research GroupReliable detection of viral DNA in stored newborn screening cards (NSC) would give important insight into possible silent infection during pregnancy and around birth. We sought a DNA extraction method with sufficient sensitivity to detect low copy numbers of viral DNA from small punch samples of NSC. Blank NSC were spotted with seronegative EDTA-blood and seropositive EBV EDTA-blood. DNA was extracted with commercial and noncommercial DNA extraction methods and quantified on a spectrofluorometer using a PicoGreen dsDNA quantification kit. Serial dilutions of purified viral DNA controls determined the sensitivity of the amplification protocol, and seropositive EBV EDTA-blood amplified by nested PCR (nPCR) validated the DNA extraction methods. There were considerable differences between the commercial and noncommercial DNA extraction methods (P=0.014; P=0.016). Commercial kits compared favorably, but the QIamp DNA micro kit with an added forensic filter step was marginally more sensitive. The mean DNA yield from this method was 3 ng/μl. The limit of detection was 10 viral genome copies in a 50-μl reaction. EBV nPCR detection in neat and 1:10 diluted DNA extracts could be replicated reliably. We conclude that the QIamp Micro DNA extraction method with the added forensic spin-filter step was suitable for retrospective DNA viral assays from NSC.
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