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Cerebral palsy (CP) represents a group of non-progressive clinically heterogeneous disorders that are characterized by motor impairment and early age of onset, frequently accompanied by co-morbidities. The cause of CP has historically been attributed to environmental stressors resulting in brain damage. While genetic risk factors are also implicated, guidelines for diagnostic assessment of CP do not recommend for routine genetic testing. Given numerous reports of aetiologic copy number variations (CNVs) in other neurodevelopmental disorders, we used microarrays to genotype a population-based prospective cohort of children with CP and their parents. Here we identify de novo CNVs in 8/115 (7.0%) CP patients (∼1% rate in controls). In four children, large chromosomal abnormalities deemed likely pathogenic were found, and they were significantly more likely to have severe neuromotor impairments than those CP subjects without such alterations. Overall, the CNV data would have impacted our diagnosis or classification of CP in 11/115 (9.6%) families. Cerebral palsy (CP) is a heterogeneous disorder that has been historically attributed to environmental factors with genetic contributions being discovered more recently. Here the authors perform microarray-based analysis of copy number variations in a cohort of children with CP and their parents and find chromosomal abnormalities linked to the disease.

Aim  Traditionally, cerebral palsy (CP) had been classified according to the distribution and quality of motor impairment. A standardized functional classification of gross motor skills has recently been validated – the Gross Motor Function Classification System (GMFCS). The relationship between the neurological subtype of CP and GMFCS level remains undefined in CP. Method  The Quebec Cerebral Palsy Registry (Registre de la paralysie cérébrale au Québec [REPACQ]) over a 4‐year birth interval (1999–2002 inclusive) identified 301 children with CP. Information on both CP subtype and GMFCS level was available for 243 children (138 males, 105 females) with final data extraction at a mean age of 44 months (SD 14mo, range 24–79mo). Proportions of children with a particular CP subtype at GMFCS levels I to III versus levels IV to V were determined and compared. Results  CP subtype versus GMFCS levels I to III or IV to V was distributed proportionally as follows: spastic diplegic, 51/52 (98%) versus 1/52 (2%); spastic quadriparetic, 20/85 (24%) versus 65/85 (76%); spastic hemiplegic, 76/77 (99%) versus 1/77 (1%); dyskinetic, 4/16 (25%) versus 12/16 (75%); other (triplegic or ataxic–hypotonic), 10/13 (77%) versus 3/13 (23%). These distributions (proportions) all yielded significant (p<0.001) Pearson χ2 values. Interpretation Neurological subtype is a powerful predictor of functional status related to ambulation. This has implications for counseling families.

Global Developmental Delay (GDD) and Intellectual Disability (ID) are two of the most common presentations encountered by physicians taking care of children. GDD/ID is classified into non-syndromic GDD/ID, where GDD/ID is the sole evident clinical feature, or syndromic GDD/ID, where there are additional clinical features or co-morbidities present. Careful evaluation of children with GDD and ID, starting with detailed history followed by a thorough examination, remain the cornerstone for etiologic diagnosis. However, when initial history and examination fail to identify a probable underlying etiology, further genetic testing is warranted. In recent years, genetic testing has been shown to be the single most important diagnostic modality for clinicians evaluating children with non-syndromic GDD/ID. In this review, we discuss different genetic testing currently available, review common underlying copy-number variants and molecular pathways, explore the recent evidence and recommendations for genetic evaluation and discuss an approach to the diagnosis and management of children with non-syndromic GDD and ID.

Aim  Microarray technology has a significantly higher clinical yield than karyotyping in individuals with global developmental delay (GDD). Despite this, it has not yet been routinely implemented as a screening test owing to the perception that this approach is more expensive. We aimed to evaluate the effect that replacing karyotype with array‐based comparative genomic hybridization (aCGH) would have on the total cost of the workup for GDD. Method  We evaluated the cost‐effectiveness of aCGH compared with karyotyping by retrospectively analysing the cost of workup in a cohort of 114 children (69 males; 45 females) representing a consecutive series of children diagnosed with GDD. Results  The average increase in cost if aCGH had been performed instead of karyotyping as a first test was$442 per individual when performed by a private company (98% confidence interval $ 238–604). In contrast,$106 (98% confidence interval −$ 17 to$195) would have been saved if aCGH was performed locally in a laboratory already possessing the required technology. The incremental cost per additional diagnosis was estimated to be $ 12 874 if aCGH was performed in a private laboratory, but <$1379 if performed locally. (Costs reported in Canadian dollars, using 2010 prices.) Interpretation  aCGH would be cost‐effective as a first genetic test in the clinical evaluation of individuals with GDD.

The objective of this study was to determine the major comorbidities in patients with spastic quadriplegic (SQ) cerebral palsy (CP) and their possible clinical associations. Medical records of patients with SQ CP from a pediatric neurology practice over a 14‐year period were retrospectively and systematically reviewed. Variables examined included demographics, prenatal, perinatal, and postnatal risk factors. Comorbidities documented included those involving hearing, vision, feeding status, and epilepsy. Binomial logistic regression analyses were applied to identify clinical associations of the comorbidities. Ninety‐two children were included in this study of whom 39 were born preterm. Mean age of presentation was 2 months (SD 3.5) and males comprised 60% of the group. A total of 57% had a Gross Motor Function Classification Score (GMFCS) of Level IV or V. The four documented comorbidities occurred at a high frequency: 66 out of 83 children (80%) had a visual impairment with 13 (21%) having a substantial impairment; 37 out of 86 children (40%) had a hearing deficit; 43 out of 92 children (47%) had epilepsy; and 29 (33%) required assisted feeding. A GMFCS Level of IV or V and documented microcephaly was associated with the need for assisted feeding (odds ratio [OR] 8.1; 95% confidence interval [CI] 2.1‐29.8, p=0.002 and OR 4.9, 95% CI 1.7‐14.8, p=0.004 respectively). Epilepsy was associated with the occurrence of neonatal encephalopathy (OR 2.3, 95% CI 1.0‐55; p=0.05), microcephaly (OR 4.9, 95% CI 1.6‐14.8; p=0.004), periventricular leukomalacia (OR 7.4, 95% CI 1.6‐35.0; p=0.012), and perinatal asphyxia (OR 3.6, 95% CI 1.5‐8.9; p=0.005). There is a high frequency of comorbidity in the setting of SQ CP which can impact on quality of life and burdens of care. Few clinical associations of this burden appear, thus necessitating systematic programmatic follow‐up of these children to facilitate early identification and intervention.

BackgroundAn equitable and affordable healthcare system requires a constant search for the optimal way to deliver increasingly expensive neonatal care. Therefore, evaluating the impact of hospital intensity around birth on long-term health outcomes is necessary if we are to assess the value of high intensity neonatal care against its costs.MethodsThis study exploits uneven geographical distribution of high intensity birth hospitals across Canada to generate comparisons across similar Cerebral Palsy (CP) related births treated at hospitals with different intensities. We employ a rich dataset from the Canadian Multi-Regional CP Registry (CCPR) and instrumental variables related to the mother’s location of residence around birth.ResultsWe find that differences in hospitals’ intensities are not associated with differences in clinically relevant, long-term CP health outcomes.ConclusionsOur results suggest that existing matching mechanism of births to hospitals within large metropolitan areas could be improved by early detection of high risk births and subsequent referral of these births to high intensity birthing centers. Substantial hospitalization costs might be averted to Canadian healthcare system ($16 million with a 95% CI of $6,131,184 - $24,103,478) if CP related births were assigned to low intensity hospitals and subsequently transferred if necessary to high intensity hospitals.

Background Inborn errors of metabolism (IEMs) have been anecdotally reported in the literature as presenting with features of cerebral palsy (CP) or misdiagnosed as ‘atypical CP’. A significant proportion is amenable to treatment either directly targeting the underlying pathophysiology (often with improvement of symptoms) or with the potential to halt disease progression and prevent/minimize further damage. Methods We performed a systematic literature review to identify all reports of IEMs presenting with CP-like symptoms before 5 years of age, and selected those for which evidence for effective treatment exists. Results We identified 54 treatable IEMs reported to mimic CP, belonging to 13 different biochemical categories. A further 13 treatable IEMs were included, which can present with CP-like symptoms according to expert opinion, but for which no reports in the literature were identified. For 26 of these IEMs, a treatment is available that targets the primary underlying pathophysiology ( e.g. neurotransmitter supplements), and for the remainder (n = 41) treatment exerts stabilizing/preventative effects ( e.g . emergency regimen). The total number of treatments is 50, and evidence varies for the various treatments from Level 1b, c (n = 2); Level 2a, b, c (n = 16); Level 4 (n = 35); to Level 4–5 (n = 6); Level 5 (n = 8). Thirty-eight (57%) of the treatable IEMs mimicking CP can be identified by ready available metabolic screening tests in blood or urine, while the remaining IEMs require more specific and sometimes invasive tests. Conclusions Limited by the rare nature of IEMs and incomplete information in the literature, we conclude that (1) A surprisingly large number of IEMs can present with CP symptoms, as ‘CP mimics’, (2) although individually rare, a large proportion of these diseases are treatable such that neurological damage can either be reversed or prevented, (3) clinician awareness of treatable CP mimics is important for appropriate screening, diagnosis, and early intervention, and (4) systematic studies are required to elucidate the collective frequency of treatable IEMs in CP.

Neonatal encephalopathy following birth asphyxia is a major predictor of long-term neurological impairment. Therapeutic hypothermia is currently the standard of care to prevent brain injury in asphyxiated newborns but is not protective in all cases. More robust and versatile treatment options are needed. Angiogenesis is a demonstrated therapeutic target in adult stroke. However, no systematic study examines the expression of angiogenesis-related markers following birth asphyxia in human newborns. This study aimed to evaluate the expression of angiogenesis-related protein markers in asphyxiated newborns developing and not developing brain injury compared to healthy control newborns. Twelve asphyxiated newborns treated with hypothermia were prospectively enrolled; six developed eventual brain injury and six did not. Four healthy control newborns were also included. We used Rules-Based Medicine multi-analyte profiling and protein array technologies to study the plasma concentration of 49 angiogenesis-related proteins. Mean protein concentrations were compared between each group of newborns. Compared to healthy newborns, asphyxiated newborns not developing brain injury showed up-regulation of pro-angiogenic proteins, including fatty acid binding protein-4, glucose-6-phosphate isomerase, neuropilin-1, and receptor tyrosine-protein kinase erbB-3; this up-regulation was not evident in asphyxiated newborns eventually developing brain injury. Also, asphyxiated newborns developing brain injury showed a decreased expression of anti-angiogenic proteins, including insulin-growth factor binding proteins -1, -4, and -6, compared to healthy newborns. These findings suggest that angiogenesis pathways are dysregulated following birth asphyxia and are putatively involved in brain injury pathology and recovery.