Cerebellar hypoplasia (CH) refers to a cerebellum of reduced volume with preserved shape. CH is associated with a broad heterogeneity in neuroradiologic features, etiologies, clinical ...characteristics, and neurodevelopmental outcomes, challenging physicians evaluating children with CH. Traditionally, neuroimaging has been a key tool to categorize CH based on the pattern of cerebellar involvement (e.g., hypoplasia of cerebellar vermis only vs. hypoplasia of both the vermis and cerebellar hemispheres) and the presence of associated brainstem and cerebral anomalies. With the advances in genetic technologies of the recent decade, many novel CH genes have been identified, and consequently, a constant updating of the literature and revision of the classification of cerebellar malformations are needed. Here, we review the current literature on CH. We propose a systematic approach to recognize specific neuroimaging patterns associated with CH, based on whether the CH is isolated or associated with posterior cerebrospinal fluid anomalies, specific brainstem or cerebellar malformations, brainstem hypoplasia with or without cortical migration anomalies, or dysplasia. The CH radiologic pattern and clinical assessment will allow the clinician to guide his investigations and genetic testing, give a more precise diagnosis, screen for associated comorbidities, and improve prognostication of associated neurodevelopmental outcomes.
Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of de novo mutations (DNMs) in ID but the extent to which they ...contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown. Here, we report a screen for DNMs in subjects with moderate or severe ID. We sequenced the exomes of 41 probands and their parents, and confirmed 81 DNMs affecting the coding sequence or consensus splice sites (1.98 DNMs/proband). We observed a significant excess of de novo single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects, suggesting that at least a subset of these variations are pathogenic. A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (HNRNPU, WAC, RYR2, SET, EGR1, MYH10, EIF2C1, COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B) that have not previously been causally linked to ID. Interestingly, no case was explained by inherited mutations. Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID. We conclude that DNMs represent a major cause of moderate or severe ID.
There are growing concerns that antenatal corticosteroid administration may harm children's neurodevelopment. We investigated the safety of antenatal corticosteroid administration practices for ...children's overall developmental health (skills and behaviors) at early school age.
We linked population health and education databases from British Columbia (BC), Canada to identify a cohort of births admitted to hospital between 31 weeks, 0 days gestation (31+0 weeks), and 36+6 weeks, 2000 to 2013, with routine early school age child development testing. We used a regression discontinuity design to compare outcomes of infants admitted just before and just after the clinical threshold for corticosteroid administration of 34+0 weeks. We estimated the median difference in the overall Early Development Instrument (EDI) score and EDI subdomain scores, as well as risk differences (RDs) for special needs designation and developmental vulnerability (<10th percentile on 2 or more subdomains). The cohort included 5,562 births admitted between 31+0 and 36+6 weeks, with a median EDI score of 40/50. We found no evidence that antenatal corticosteroid administration practices were linked with altered child development at early school age: median EDI score difference of -0.5 95% CI: -2.2 to 1.7 (p = 0.65), RD per 100 births for special needs designation -0.5 -4.2 to 3.1 (p = 0.96) and for developmental vulnerability of 3.9 95% CI:-2.2 to 10.0 (p = 0.24). A limitation of our study is that the regression discontinuity design estimates the effect of antenatal corticosteroid administration at the gestational age of the discontinuity, 34 + 0 weeks, so our results may become less generalisable as gestational age moves further away from this point.
Our study did not find that that antenatal corticosteroid administration practices were associated with child development at early school age. Our findings may be useful for supporting clinical counseling about antenatal corticosteroids administration at late preterm gestation, when the balance of harms and benefits is less clear.
PLPHP (pyridoxal-phosphate homeostasis protein) deficiency is caused by biallelic pathogenic variants in
PLPBP
and is a rare cause of pyridoxine-responsive disorders. We describe three ...French-Canadian individuals with PLPHP deficiency, including one with unusual paroxysmal episodes lacking EEG correlation with a suspicious movement disorder, rarely reported in B6RDs. In addition, we review the clinical features and treatment responses of all 51 previously published individuals with PLPHP deficiency. Our case series underlines the importance of considering
PLPBP
mutations in individuals with partially B6-responsive seizures and highlights the presence of a founder effect in the French-Canadian population.
Oligodendrocyte (OL) injury and subsequent loss is a pathologic hallmark of multiple sclerosis (MS). Stress granules (SGs) are membrane-less organelles containing mRNAs stalled in translation and ...considered as participants of the cellular response to stress. Here we show SGs in OLs in active and inactive areas of MS lesions as well as in normal-appearing white matter. In cultures of primary human adult brain derived OLs, metabolic stress conditions induce transient SG formation in these cells. Combining pro-inflammatory cytokines, which alone do not induce SG formation, with metabolic stress results in persistence of SGs. Unlike sodium arsenite, metabolic stress induced SG formation is not blocked by the integrated stress response inhibitor. Glycolytic inhibition also induces persistent SGs indicating the dependence of SG formation and disassembly on the energetic glycolytic properties of human OLs. We conclude that SG persistence in OLs in MS reflects their response to a combination of metabolic stress and pro-inflammatory conditions.
Hereditary sensory and autonomic neuropathy type II (HSANII) is a rare autosomal-recessive disorder characterized by peripheral nerve degeneration resulting in a severe distal sensory loss. Although ...mutations in FAM134B and the HSN2 exon of WNK1 were associated with HSANII, the etiology of a substantial number of cases remains unexplained. In addition, the functions of WNK1/HSN2 and FAM134B and their role in the peripheral nervous system remain poorly understood. Using a yeast two-hybrid screen, we found that KIF1A, an axonal transporter of synaptic vesicles, interacts with the domain encoded by the HSN2 exon. In parallel to this screen, we performed genome-wide homozygosity mapping in a consanguineous Afghan family affected by HSANII and identified a unique region of homozygosity located on chromosome 2q37.3 and spanning the KIF1A gene locus. Sequencing of KIF1A in this family revealed a truncating mutation segregating with the disease phenotype. Subsequent sequencing of KIF1A in a series of 112 unrelated patients with features belonging to the clinical spectrum of ulcero-mutilating sensory neuropathies revealed truncating mutations in three additional families, thus indicating that mutations in KIF1A are a rare cause of HSANII. Similarly to WNK1 mutations, pathogenic mutations in KIF1A were almost exclusively restricted to an alternatively spliced exon. This study provides additional insights into the molecular pathogenesis of HSANII and highlights the potential biological relevance of alternative splicing in the peripheral sensory nervous system.
Holoprosencephaly (HPE) is the most common malformation of the prosencephalon in humans. It is characterized by a continuum of structural brain anomalies resulting from the failure of midline ...cleavage of the prosencephalon. The three classic subtypes of HPE are alobar, semilobar and lobar, although a few additional categories have been added to this original classification. The severity of the clinical phenotype is broad and usually mirrors the radiologic and associated facial features. The etiology of HPE includes both environmental and genetic factors. Disruption of sonic hedgehog (SHH) signaling is the main pathophysiologic mechanism underlying HPE. Aneuploidies, chromosomal copy number variants and monogenic disorders are identified in a large proportion of HPE patients. Despite the high postnatal mortality and the invariable presence of developmental delay, recent advances in diagnostic methods and improvements in patient management over the years have helped to increase survival rates. In this review, we provide an overview of the current knowledge related to HPE, and discuss the classification, clinical features, genetic and environmental etiologies and management.
Microglia are tissue resident macrophages with a wide range of critically important functions in central nervous system development and homeostasis.
In this study, we aimed to characterize the ...transcriptional landscape of ex vivo human microglia across different developmental ages using cells derived from pre-natal, pediatric, adolescent, and adult brain samples. We further confirmed our transcriptional observations using ELISA and RNAscope.
We showed that pre-natal microglia have a distinct transcriptional and regulatory signature relative to their post-natal counterparts that includes an upregulation of phagocytic pathways. We confirmed upregulation of CD36, a positive regulator of phagocytosis, in pre-natal samples compared to adult samples in situ. Moreover, we showed adult microglia have more pro-inflammatory signature compared to microglia from other developmental ages. We indicated that adult microglia are more immune responsive by secreting increased levels of pro-inflammatory cytokines in response to LPS treatment compared to the pre-natal microglia. We further validated in situ up-regulation of IL18 and CXCR4 in human adult brain section compared to the pre-natal brain section. Finally, trajectory analysis indicated that the transcriptional signatures adopted by microglia throughout development are in response to a changing brain microenvironment and do not reflect predetermined developmental states.
In all, this study provides unique insight into the development of human microglia and a useful reference for understanding microglial contribution to developmental and age-related human disease.
Joubert syndrome (JBTS) is an autosomal-recessive disorder characterized by a distinctive mid-hindbrain malformation, developmental delay with hypotonia, ocular-motor apraxia, and breathing ...abnormalities. Although JBTS was first described more than 40 years ago in French Canadian siblings, the causal mutations have not yet been identified in this family nor in most French Canadian individuals subsequently described. We ascertained a cluster of 16 JBTS-affected individuals from 11 families living in the Lower St. Lawrence region. SNP genotyping excluded the presence of a common homozygous mutation that would explain the clustering of these individuals. Exome sequencing performed on 15 subjects showed that nine affected individuals from seven families (including the original JBTS family) carried rare compound-heterozygous mutations in C5ORF42. Two missense variants (c.4006C>T p.Arg1336Trp and c.4690G>A p.Ala1564Thr) and a splicing mutation (c.7400+1G>A), which causes exon skipping, were found in multiple subjects that were not known to be related, whereas three other truncating mutations (c.6407del p.Pro2136Hisfs∗31, c.4804C>T p.Arg1602∗, and c.7477C>T p.Arg2493∗) were identified in single individuals. None of the unaffected first-degree relatives were compound heterozygous for these mutations. Moreover, none of the six putative mutations were detected among 477 French Canadian controls. Our data suggest that mutations in C5ORF42 explain a large portion of French Canadian individuals with JBTS.
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.
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