Trends in Prevalence and Severity of Pre/Perinatal Cerebral Palsy Among Children Born Preterm From 2004 to 2010: A SCPE Collaboration Study.

Aim: To report on prevalence of cerebral palsy (CP), severity rates, and types of brain lesions in children born preterm 2004 to 2010 by gestational age groups. Methods: Data from 12 population-based registries of the Surveillance of Cerebral Palsy in Europe network were used. Children with CP were eligible if they were born preterm (<37 weeks of gestational age) between 2004 and 2010, and were at least 4 years at time of registration. Severity was assessed using the impairment index. The findings of postnatal brain imaging were classified according to the predominant pathogenic pattern. Prevalences were estimated per 1,000 live births with exact 95% confidence intervals within each stratum of gestational age: ≤27, 28-31, 32-36 weeks. Time trends of both overall prevalence and prevalence of severe CP were investigated using multilevel negative binomial regression models. Results: The sample comprised 2,273 children. 25.8% were born from multiple pregnancies. About 2-thirds had a bilateral spastic CP. 43.5% of children born ≤27 weeks had a high impairment index compared to 37.0 and 38.5% in the two other groups. Overall prevalence significantly decreased (incidence rate ratio per year: 0.96 [0.92-1.00[) in children born 32-36 weeks. We showed a decrease until 2009 for children born 28-31 weeks but an increase in 2010 again, and a steady prevalence (incidence rate ratio per year = 0.97 [0.92-1.02] for those born ≤27 weeks. The prevalence of the most severely affected children with CP revealed a similar but not significant trend to the overall prevalence in the corresponding GA groups. Predominant white matter injuries were more frequent in children born <32 weeks: 81.5% (≤27 weeks) and 86.4% (28-31 weeks), compared to 63.6% for children born 32-36 weeks. Conclusion: Prevalence of CP in preterm born children continues to decrease in Europe excepting the extremely immature children, with the most severely affected children showing a similar trend.

Generation of two iPSC lines derived from two unrelated patients with Gaucher disease.

Gaucher disease is the most common autosomal recessive lysosomal storage disorder, caused by mutations in the ß-glucocerebrosidase gene GBA. Here we describe generation of iPSC from skin-derived fibroblasts from two unrelated individuals with neuronopathic forms of Gaucher disease. The donor for line iPSC-GBA-1, a 21 month old girl, carried the recurring GBA mutation c.1448 T > C, p.Leu483Pro at homozygous state; fibroblasts for line iPS-GBA-2 were obtained from a 4 year old girl compound heterozygous for the GBA mutations c.667 T > C, p.Trp223Arg and c.1226A > G, p.Asn409Ser. iPSCs were developed using integration free episomal vectors (OCT4, KLF4; L-MYC, SOX2 (OSKM) and LIN28). Resource table.

Late onset Krabbe disease due to the new GALC p.Ala543Pro mutation, with intriguingly high residual GALC activity in vitro.

BACKGROUND: Krabbe disease (KD) is an inherited leukodystrophy due to a defect in the GALC gene which encodes the lysosomal galactosylceramide ß-galactosidase (GALC). About two thirds of patients show the early onset form of KD dominated by cerebral demyelination leading to death in early infancy. Late onset forms include a spectrum of late infantile, juvenile and adult clinical courses. The deficiency of GALC leads to a galactosylceramide lipidosis in which lysosomal storage phenomena are seen almost only at the ultrastructural level. RESULTS: In a 4-year-old boy, the clinical suspicion of KD was high according to neurologic and neuroimaging findings. However, laboratory results were inconclusive; white blood cell GALC activity being at 23 to 25% of the normal level, and GALC genotyping revealing the new homozygous p.Ala543Pro variant which, ex silico, was of unclear significance. Studying a skin biopsy, cultured fibroblasts showed the GALC activity at 21 to 30% of the normal level; ultrastructurally, clearly KD-specific inclusions were seen in the eccrine sweat gland cells, confirming a KD diagnosis. CONCLUSION: The high clinical suspicion combined with the morphologic evidence for KD predict that the p.Ala543Pro variant is pathogenic for (late onset) KD. A hypothesis linked to the proline in the mutant GALC may explain the in vitro effect with high residual GALC activity. This patient would not have been correctly diagnosed, despite the strong clinical criteria of KD, if the electron microscopic results had not been available. The detailed knowledge of neurologic and neuroimaging signs is important in diagnostically problematic KD patients in which also an electron microscopic approach can be crucial.

PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.

Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targeted-panel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.

The second report of a new hypomyelinating disease due to a defect in the VPS11 gene discloses a massive lysosomal involvement.

Vesicular protein sorting-associated proteins (VPS, including VPS11) are indispensable in the endocytic network, in particular the endosome-lysosome biogenesis. Exome sequencing revealed the homozygous variant p.Leu387_ Gly395del in the VPS11 gene in two siblings. On immunoblotting, the mutant VPS11 protein showed a distinctly reduced immunostaining intensity. The children presented with primary and severe developmental delay associated with myoclonic seizures, spastic tetraplegia, trunk and neck hypotonia, blindness, hearing loss, and microcephaly. Neuro-imaging showed severe hypomyelination affecting cerebral and cerebellar white matter and corpus callosum, in the absence of a peripheral neuropathy. Electron microscopy of a skin biopsy revealed clusters of membranous cytoplasmic bodies in dermal unmyelinated nerve axons, and numbers of vacuoles in eccrine sweat glands, similar to what is seen in a classic lysosomal storage disease (LSD). Bone marrow cytology showed a high number of storage macrophages with a micro-vacuolated cytoplasm. Biochemically, changes in urinary glycosphingolipids were reminiscent of those in prosaposin deficiency (another LSD). The clinical and neuro-imaged features in our patients were almost identical to those in some recently reported patients with another variant in the VPS11 gene, p.Cys846Gly; underlining the presumed pathogenic potential of VPS11 defects. A new feature was the morphological evidence for lysosomal storage in VPS11 deficiency: This newly characterised disease can be viewed as belonging to the complex field of LSD.

Processing of non-canonical word-order: a case-series on lesion-induced reorganized language and age-effects in typical development.

Complex grammatical structures are mastered late in language acquisition. We studied age-effects on performance in object topicalization in 48 typically developing German-speaking participants (aged 8-30years) and in five patients (children and adolescents) with lesion-induced atypical language representation. Production was tested by a sentence repetition task, comprehension by an acting out task. Three topicalized conditions with differing disambiguation (agreement, case, and case plus agreement) were contrasted with canonical control sentences. Children's (aged 8-13years) performance was significantly below that of adolescents and adults in all topicalized conditions. All participants made most mistakes in the agreement condition. Patients showed remarkable difficulties as compared with age-appropriate control groups in all topicalization conditions and across age-groups. Despite the small sample size, the consistency of these difficulties might hint to the importance of an intact typical neural language substrate for processing complex grammatical structures even in very early brain lesions.

Language comprehension vs. language production: age effects on fMRI activation.

Normal language acquisition is a process that unfolds with amazing speed primarily in the first years of life. However, the refinement of linguistic proficiency is an ongoing process, extending well into childhood and adolescence. An increase in lateralization and a more focussed productive language network have been suggested to be the neural correlates of this process. However, the processes underlying the refinement of language comprehension are less clear. Using a language comprehension (Beep Stories) and a language production (Vowel Identification) task in fMRI, we studied language representation and lateralization in 36 children, adolescents, and young adults (age 6-24 years). For the language comprehension network, we found a more focal activation with age in the bilateral superior temporal gyri. No significant increase of lateralization with age could be observed, so the neural basis of language comprehension as assessed with the Beep Stories task seems to be established in a bilateral network by late childhood. For the productive network, however, we could confirm an increase with age both in focus and lateralization. Only in the language comprehension task did verbal IQ correlate with lateralization, with higher verbal IQ being associated with more right-hemispheric involvement. In some subjects (24%), language comprehension and language production were lateralized to opposite hemispheres.

Cerebral palsy and congenital malformations.

AIM: To determine the proportion of children with cerebral palsy (CP) who have cerebral and non-cerebral congenital malformations. METHODS: Data from 11 CP registries contributing to the European Cerebral Palsy Database (SCPE), for children born in the period 1976-1996. The malformations were classified as recognized syndromes, chromosomal anomalies, cerebral malformations or non-cerebral malformations. Prevalence of malformations was compared to published data on livebirths from a European database of congenital malformations (EUROCAT). RESULTS: Overall 547 out of 4584 children (11.9%) with CP were reported to have a congenital malformation. The majority (8.6% of all children) were diagnosed with a cerebral malformation. The most frequent types of cerebral malformations were microcephaly and hydrocephaly. Non-cerebral malformations were present in 97 CP children and in further 14 CP children with cerebral malformations. The most frequent groups of non-cerebral malformations were cardiac, facial clefts and limb and skeleton malformations. Children born at term had a significantly higher prevalence of cerebral malformations compared to children born before 32 weeks (12.1% versus 2.1%, p<0.001). CONCLUSION: Cerebral malformations were much more frequent among children with CP than among all livebirths in the population. Malformations in organ systems close to the brain (eye, facial clefts) were more frequent in the CP population while malformations in organ systems further from the brain (renal, genital) were more frequent in the general population.

Trends in cerebral palsy among infants of very low birthweight (<1500 g) or born prematurely (<32 weeks) in 16 European centres: a database study.

BACKGROUND: The risk of cerebral palsy, the commonest physical disability of children in western Europe, is higher in infants of very low birthweight (VLBW)--those born weighing less than 1500 g--and those from multiple pregnancies than in infants of normal birthweight. An increasing proportion of infants from both of these groups survive into childhood. This paper describes changes in the frequency and distribution of cerebral palsy by sex and neurological subtype in infants with a birthweight below 1000 g and 1000-1499 g in the period 1980-96. METHODS: A group of 16 European centres, Surveillance of Cerebral Palsy in Europe, agreed a standard definition of cerebral palsy and inclusion and exclusion criteria. Data for children with cerebral palsy born in the years 1980-96 were pooled. The data were analysed to describe the distribution and prevalence of cerebral palsy in VLBW infants. Prevalence trends were expressed as both per 1000 livebirths and per 1000 neonatal survivors. FINDINGS: There were 1575 VLBW infants born with cerebral palsy; 414 (26%) were of birthweight less than 1000 g and 317 (20%) were from multiple pregnancies. 1426 (94%) had spastic cerebral palsy, which was unilateral (hemiplegic) in 336 (24%). The birth prevalence fell from 60.6 (99%CI 37.8-91.4) per 1000 liveborn VLBW infants in 1980 to 39.5 (28.6-53.0) per 1000 VLBW infants in 1996. This decline was related to a reduction in the frequency of bilateral spastic cerebral palsy among infants of birthweight 1000-1499 g. The frequency of cerebral palsy was higher in male than female babies in the group of birthweight 1000-1499 g (61.0 [53.8-68..2] vs 49.5 [42.8-56.2] per 1000 livebirths; p=0.0025) but not in the group of birthweight below 1000 g. INTERPRETATION: These data from a large population base provide evidence that the prevalence of cerebral palsy in children of birthweight less than 1500 g has fallen, which has important implications for parents, health services, and society.

Lesion-induced right-hemispheric language and organization of nonverbal functions.

Early left-hemispheric brain lesions may lead to a reorganization of language into the right hemisphere. Language functions are consecutively spared, but visuospatial functions show slight deficits. Cortical 'crowding' of the right hemisphere has been suggested as an explanation for this effect, but no direct evidence has as yet been put forward. We examined six patients with early left-hemispheric brain lesions and subsequent right-hemispheric language organization with functional magnetic resonance imaging and compared their activation patterns in a verbal and two nonverbal tasks with the patterns of six controls. In the patient group, nonverbal functions were reorganized neither interhemispherically nor intrahemispherically. Instead, verbal and nonverbal functions were mediated by a common right-hemispheric network. This argues in favour of the 'crowding hypothesis'.