Search

Purpose and scopeThe aim of this position statement is to provide recommendations for clinicians regarding the use of genetic and metabolic investigations for patients with neurodevelopmental disorders (NDDs), specifically, patients with global developmental delay (GDD), intellectual disability (ID) and/or autism spectrum disorder (ASD). This document also provides guidance for primary care and non-genetics specialists caring for these patients while awaiting consultation with a clinical geneticist or metabolic specialist.Methods of statement developmentA multidisciplinary group reviewed existing literature and guidelines on the use of genetic and metabolic investigations for the diagnosis of NDDs and synthesised the evidence to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and to the Canadian Pediatric Society (Mental Health and Developmental Disabilities Committee); following incorporation of feedback, it was approved by the CCMG Board of Directors on 1 September 2022.Results and conclusionsChromosomal microarray is recommended as a first-tier test for patients with GDD, ID or ASD. Fragile X testing should also be done as a first-tier test when there are suggestive clinical features or family history. Metabolic investigations should be done if there are clinical features suggestive of an inherited metabolic disease, while the patient awaits consultation with a metabolic physician. Exome sequencing or a comprehensive gene panel is recommended as a second-tier test for patients with GDD or ID. Genetic testing is not recommended for patients with NDDs in the absence of GDD, ID or ASD, unless accompanied by clinical features suggestive of a syndromic aetiology or inherited metabolic disease.

Morphological and emerging molecular studies have provided evidence for heterogeneity within the oligodendrocyte population. To address the regional and age-related heterogeneity of human mature oligodendrocytes (MOLs) we applied single-cell RNA sequencing to cells isolated from cortical/subcortical, subventricular zone brain tissue samples, and thoracolumbar spinal cord samples. Unsupervised clustering of cells identified transcriptionally distinct MOL subpopulations across regions. Spinal cord MOLs, but not microglia, exhibited cell-type-specific upregulation of immune-related markers compared to the other adult regions. SVZ MOLs showed an upregulation of select number of development-linked transcription factors compared to other regions; however, pseudotime trajectory analyses did not identify a global developmental difference. Age-related analysis of cortical/subcortical samples indicated that pediatric MOLs, especially from under age 5, retain higher expression of genes linked to development and to immune activity with pseudotime analysis favoring a distinct developmental stage. Our regional and age-related studies indicate heterogeneity of MOL populations in the human CNS that may reflect developmental and environmental influences.

Contactin-associated protein-like 2 (CNTNAP2) gene encodes for CASPR2, a presynaptic type 1 transmembrane protein, involved in cell–cell adhesion and synaptic interactions. Biallelic CNTNAP2 loss has been associated with “Pitt-Hopkins-like syndrome-1” (MIM#610042), while the pathogenic role of heterozygous variants remains controversial. We report 22 novel patients harboring mono- (n = 2) and bi-allelic (n = 20) CNTNAP2 variants and carried out a literature review to characterize the genotype–phenotype correlation. Patients (M:F 14:8) were aged between 3 and 19 years and affected by global developmental delay (GDD) (n = 21), moderate to profound intellectual disability (n = 17) and epilepsy (n = 21). Seizures mainly started in the first two years of life (median 22.5 months). Antiseizure medications were successful in controlling the seizures in about two-thirds of the patients. Autism spectrum disorder (ASD) and/or other neuropsychiatric comorbidities were present in nine patients (40.9%). Nonspecific midline brain anomalies were noted in most patients while focal signal abnormalities in the temporal lobes were noted in three subjects. Genotype–phenotype correlation was performed by also including 50 previously published patients (15 mono- and 35 bi-allelic variants). Overall, GDD (p p p = 0.012), ASD (p = 0.009), language impairment (p = 0.020) and severe cognitive impairment (p = 0.031) were significantly associated with the presence of biallelic versus monoallelic variants. We have defined the main features associated with biallelic CNTNAP2 variants, as severe cognitive impairment, epilepsy and behavioral abnormalities. We propose CASPR2-deficiency neurodevelopmental disorder as an exclusively recessive disease while the contribution of heterozygous variants is less likely to follow an autosomal dominant inheritance pattern.

Mirror movements (MM) disorder is characterized by involuntary movements on one side of the body that mirror intentional movements on the opposite side. We performed genetic characterization of a family with autosomal dominant MM and identified ARHGEF7 , a RhoGEF, as a candidate MM gene. We found that Arhgef7 and its partner Git1 bind directly to Dcc. Dcc is the receptor for Netrin-1, an axon guidance cue that attracts commissural axons to the midline, promoting the midline crossing of axon tracts. We show that Arhgef7 and Git1 are required for Netrin-1–mediated axon guidance and act as a multifunctional effector complex. Arhgef7/Git1 activates Rac1 and Cdc42 and inhibits Arf1 downstream of Netrin-1. Furthermore, Arhgef7/Git1, via Arf1, mediates the Netrin-1–induced increase in cell surface Dcc. Mice heterozygous for Arhgef7 have defects in commissural axon trajectories and increased symmetrical paw placements during skilled walking, a MM-like phenotype. Thus, we have delineated how ARHGEF7 mutation causes MM.

Early multiple sclerosis lesions feature relative preservation of oligodendrocyte cell bodies with dying back retraction of their myelinating processes. Cell loss occurs with disease progression. Putative injury mediators include metabolic stress (low glucose/nutrient), pro-inflammatory mediators (interferon γ and tumour necrosis factor α), and excitotoxins (glutamate). Our objective was to compare the impact of these disease relevant mediators on the injury responses of human mature oligodendrocytes.In the current study, we determined the effects of these mediators on process extension and survival of human brain derived mature oligodendrocytes in vitro and used bulk RNA sequencing to identify distinct effector mechanisms that underlie the responses. All mediators induced significant process retraction of the oligodendrocytes in dissociated cell culture. Only metabolic stress (low glucose/nutrient) conditions resulted in delayed (4–6 days) non-apoptotic cell death. Metabolic effects were associated with induction of the integrated stress response, which can be protective or contribute to cell injury dependent on its level and duration of activation. Addition of Sephin1, an agonist of the integrated stress response induced process retraction under control conditions and further enhanced retraction under metabolic stress conditions. The antagonist ISRIB restored process outgrowth under stress conditions, and if added to already stressed cells, reduced delayed cell death and prolonged the period in which recovery could occur. Inflammatory cytokine functional effects were associated with activation of multiple signalling pathways (including Jak/Stat-1) that regulate process outgrowth, without integrated stress response induction. Glutamate application produced limited transcriptional changes suggesting a contribution of effects directly on cell processes.Our comparative studies indicate the need to consider both the specific injury mediators and the distinct cellular mechanisms of responses to them by human oligodendrocytes to identify effective neuroprotective therapies for multiple sclerosis.

Antenatal corticosteroids reduce respiratory morbidity in preterm infants, but their use during late preterm gestation (34-36 weeks) is limited because their safety for longer-term child neurodevelopment is unclear. We sought to determine if fetuses with higher probability of exposure to antenatal corticosteroids had increased rates of prescriptions for attention-deficit/hyperactivity disorder (ADHD) medication in childhood, using a quasiexperimental design that better controls for confounding than existing observational studies.We identified 16 358 children whose birthing parents were admitted for delivery between 31 + 0 (31 weeks, 0 days) and 36 + 6 weeks' gestation in 2000-2013, using a perinatal data registry from British Columbia, Canada, and linked their records with population-based child ADHD medication data (2000-2018). We used a regression discontinuity design to capitalize on the fact that pregnancies presenting for delivery immediately before and immediately after the clinical cut-off for antenatal corticosteroid administration of 34 + 0 weeks' gestation have very different levels of exposure to corticosteroids, but are otherwise similar with respect to confounders.Over a median follow-up period of 9 years, 892 (5.5%) children had 1 or more dispensations of ADHD medication. Children whose birthing parents were admitted for delivery just before the corticosteroid clinical cut-off of 34 + 0 weeks' gestation did not appear to be more likely to be prescribed ADHD medication than those admitted just after the cut-off (rate ratio 1.1, 95% confidence interval [CI] 0.8 to 1.6; 1.3 excess cases per 100 children, 95% CI -2.5 to 5.7).We found little evidence that children with higher probability of exposure to antenatal corticosteroids have higher rates of ADHD prescriptions in childhood, supporting the safety of antenatal corticosteroids for this neurodevelopmental outcome.

Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy and movement disorder. We evaluated a large cohort of patients (n = 25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor and ataxia. Later in the disease course, they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibres and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders.

Background: The term Pontocerebellar Hypoplasia (PCH) was initially used to designate a heterogeneous group of fetal-onset genetic neurodegenerative disorders. As a descriptive term, PCH refers to pons and cerebellum of reduced volume. In addition to the classic PCH types, many other disorders can result in a similar imaging appearance. Objective: To review imaging, clinical and genetic features and underlying etiologies of a cohort of children with PCH on imaging. Methods: We systematically reviewed brain images and clinical charts of 38 patients with radiologic evidence of PCH. Results: Our cohort included 21 males and 17 females, with ages ranging between 8 days to 15 years. All individuals had pons and cerebellar vermis hypoplasia, and 63% had cerebellar hemisphere hypoplasia. Supratentorial anomalies were found in 71%. An underlying etiology was identified in 65% and included chromosomal (21%), monogenic (34%) and acquired (10%) causes. Only one patient had pathogenic variants in a “classic” PCH gene. Outcomes were poor regardless of etiology, though no one had regression. Approximately one third of patients deceased at a median age of 8 months. All individuals had global developmental delay, 50% were non-verbal, 64% were non-ambulatory and 45% required gastrostomy feeding. Conclusion: Radiologic PCH has heterogenous etiologies and the “classic” PCH genes underlie only a minority of cases. Broad genetic testing, including chromosomal microarray and exome or multigene panels, is recommended in individuals with PCH-like imaging appearance. Our results strongly suggest that the term PCH should be used to designate radiologic findings, and not to imply neurogenerative disorders.

Purpose: Brain monoamine vesicular transport disease is an infantile-onset movement disorder that mimics cerebral palsy. In 2013, the homozygous SLC18A2 variant, p.Pro387Leu, was first reported as a cause of this rare disorder, and dopamine agonists were efficient for treating affected individuals from a single large family. To date, only 6 variants have been reported. In this study, we evaluated genotype–phenotype correlations in individuals with biallelic SLC18A2 variants. Methods: A total of 42 affected individuals with homozygous SLC18A2 variant alleles were identified. We evaluated genotype–phenotype correlations and the missense variants in the affected individuals based on the structural modeling of rat VMAT2 encoded by Slc18a2, with cytoplasm- and lumen-facing conformations. A Caenorhabditis elegans model was created for functional studies. Results: A total of 19 homozygous SLC18A2 variants, including 3 recurrent variants, were identified using exome sequencing. The affected individuals typically showed global developmental delay, hypotonia, dystonia, oculogyric crisis, and autonomic nervous system involvement (temperature dysregulation/sweating, hypersalivation, and gastrointestinal dysmotility). Among the 58 affected individuals described to date, 16 (28%) died before the age of 13 years. Of the 17 patients with p.Pro237His, 9 died, whereas all 14 patients with p.Pro387Leu survived. Although a dopamine agonist mildly improved the disease symptoms in 18 of 21 patients (86%), some affected individuals with p.Ile43Phe and p.Pro387Leu showed milder phenotypes and presented prolonged survival even without treatment. The C. elegans model showed behavioral abnormalities. Conclusion: These data expand the phenotypic and genotypic spectra of SLC18A2-related disorders. © 2022 American College of Medical Genetics and Genomics, National Institutes of Health, NIH: T32 GM007526-42; National Heart, Lung, and Blood Institute, NHLBI; National Human Genome Research Institute, NHGRI: K08 HG008986; National Institute of Neurological Disorders and Stroke, NINDS: R35NS105078; International Rett Syndrome Foundation, IRSF: 3701-1; Muscular Dystrophy Association, MDA: 512848; American Brain Foundation, ABF; American Academy of Neurology, AAN; Takeda Science Foundation, TSF; Japan Agency for Medical Research and Development, AMED: JP22ek0109486, JP22ek0109493, JP22ek0109549; Horizon 2020 Framework Programme, H2020; Muscular Dystrophy UK, MDUK; Multiple System Atrophy Trust, MSAT; Brain Research UK, BRUK; Baylor-Hopkins Center for Mendelian Genomics, BHCMG: UM1 HG006542; Medical Research Council, MRC: G0601943, MR/S005021/1, MR/S01165X/1; Ataxia UK; European Research Council, ERC; Rosetrees Trust; Great Ormond Street Hospital Charity, GOSH; Japan Society for the Promotion of Science, KAKEN: JP19H03621, JP20K07907, JP20K08164, JP20K16932, JP20K17936, JP21k15907; Horizon 2020: 714853, MC-A658-5TY30; University College London Hospitals Biomedical Research Centre, UCLH BRC; King Salman Center for Disability Research, KSCDR: RG-2022-010, We thank the participants and their families for their involvement in this study. This work was supported by the Japan Agency for Medical Research and Development ( AMED ) under grant numbers JP22ek0109486, JP22ek0109549, and JP22ek0109493 (N.Ma.); Japan Society for the Promotion of Science ( JSPS) KAKENHI under grant numbers JP19H03621 (N.Mi.), JP20K07907 (S.M.), JP20K08164 (T.Miz.), JP20K17936 (A.F.), JP20K16932 (K.H.), and JP21k15907 (Y.U.); and the Takeda Science Foundation (T.Miz., N.Mi., and N.Ma.). This study was partially supported by the US National Human Genome Research Institute and National Heart Lung and Blood Institute to the Baylor-Hopkins Center for Mendelian Genomics (UM1 HG006542 to J.R.L.), US National Institute of Neurological Disorders and Stroke (R35NS105078 to J.R.L.), and Muscular Dystrophy Association (512848 to J.R.L.). D.Ma. was supported by a Medical Genetics Research Fellowship Program through the National Institutes of Health (T32 GM007526-42). D.P. was supported by a Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Academy of Neurology , American Brain Foundation , and Muscle Study Group and by the International Rett Syndrome Foundation (grant number #3701-1). J.E.P. was supported by the National Human Genome Research Institute (K08 HG008986). H.H. was funded by the Medical Research Council ( MRC) (MR/S01165X/1, MR/S005021/1, and G0601943), NIHR University College London Hospitals Biomedical Research Centre , Rosetree Trust, Ataxia UK , Multiple System Atrophy Trust , Brain Research UK , Sparks Great Ormond Street Hospital Charity , Muscular Dystrophy UK , and Muscular Dystrophy Association . N.D. was supported by an MRC strategic award to establish International Centre for Genomic Medicine in Neuromuscular Diseases (MR/S005021/1). This project also received funding from the European Research Council under the European Union’s Horizon 2020 Research and Innovation Program (grant agreement number 714853) and was supported by the Medical Research Council through grant MC-A658-5TY30. We acknowledge the support of King Salman Center for Disability Research through Research Group no RG-2022-010 (F.S.A.). Figure 1A, 2A, and Graphical Abstract were created with BioRender.com ., We thank the participants and their families for their involvement in this study. This work was supported by the Japan Agency for Medical Research and Development (AMED) under grant numbers JP22ek0109486, JP22ek0109549, and JP22ek0109493 (N.Ma.); Japan Society for the Promotion of Science (JSPS) KAKENHI under grant numbers JP19H03621 (N.Mi.), JP20K07907 (S.M.), JP20K08164 (T.Miz.), JP20K17936 (A.F.), JP20K16932 (K.H.), and JP21k15907 (Y.U.); and the Takeda Science Foundation (T.Miz., N.Mi., and N.Ma.). This study was partially supported by the US National Human Genome Research Institute and National Heart Lung and Blood Institute to the Baylor-Hopkins Center for Mendelian Genomics (UM1 HG006542 to J.R.L.), US National Institute of Neurological Disorders and Stroke (R35NS105078 to J.R.L.), and Muscular Dystrophy Association (512848 to J.R.L.). D.Ma. was supported by a Medical Genetics Research Fellowship Program through the National Institutes of Health (T32 GM007526-42). D.P. was supported by a Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Academy of Neurology, American Brain Foundation, and Muscle Study Group and by the International Rett Syndrome Foundation (grant number #3701-1). J.E.P. was supported by the National Human Genome Research Institute (K08 HG008986). H.H. was funded by the Medical Research Council (MRC) (MR/S01165X/1, MR/S005021/1, and G0601943), NIHR University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, Multiple System Atrophy Trust, Brain Research UK, Sparks Great Ormond Street Hospital Charity, Muscular Dystrophy UK, and Muscular Dystrophy Association. N.D. was supported by an MRC strategic award to establish International Centre for Genomic Medicine in Neuromuscular Diseases (MR/S005021/1). This project also received funding from the European Research Council under the European Union's Horizon 2020 Research and Innovation Program (grant agreement number 714853) and was supported by the Medical Research Council through grant MC-A658-5TY30. We acknowledge the support of King Salman Center for Disability Research through Research Group no RG-2022-010 (F.S.A.). Figure 1A, 2A, and Graphical Abstract were created with BioRender.com.

SUMMARYThe axon guidance cue, Netrin-1, signals through its receptor DCC to attract commissural axons to the midline. Pathogenic variants in DCC frequently lead to congenital mirror movements (CMM), but how these variants impact DCC function is largely unknown. Screening ofDCCin individuals with CMM recently revealed a novel variant located in a conserved motif in the cytoplasmic tail of DCC that is predicted to bind to a central actin nucleation promoting factor, the WAVE regulatory complex (WRC). Here, we use biochemical and axon guidance assays to show that this CMM-associated DCC variant is pathogenic by disrupting the interaction between DCC and the WRC. This DCC-WRC interaction is evolutionarily conserved and is required for Netrin-1 mediated commissural axon outgrowth and guidance. Together, we identify the WRC as a pivotal component of Netrin-1/DCC signaling and further provide a molecular mechanism explaining how genetic variants in DCC may lead to CMM.

Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and one was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.

Summary Background Acute flaccid myelitis (AFM) is characterised by rapid onset of limb weakness with spinal cord grey-matter abnormalities on MRI scan. We aimed to assess whether detection of enterovirus in respiratory or other specimens can help predict prognosis in children with AFM. Methods In this nationwide, longitudinal study, we evaluated the significance of detection of enterovirus in any sample in predicting outcomes in a cohort of Canadian children younger than 18 years presenting with AFM to tertiary paediatric hospitals in Canada in 2014 and 2018. All patients fulfilled the 2015 US Centers for Disease Control and Prevention case definition for definite AFM or probable AFM. Clinical data, laboratory findings, treatment, and neuroimaging results were collected (follow up period up to 5 years). We assessed neurological function and motor outcomes using Kurtzke's Expanded Disability Status Scale (EDSS) and a Weakest Limb Score. Findings 58 children with AFM (median age 5·1 years, IQR 3·8–8·3) were identified across five of Canada's ten provinces and three territories. 25 (43%) children had enterovirus detected in at least one specimen: 16 (64%) with EV-D68, two (8%) with EV-A71, two (8%) with coxsackievirus, 10 (40%) with untyped enterovirus. Children who were enterovirus positive were more likely than those that were negative to have had quadriparesis (12 [48%] of 25 vs four [13%] of 30; p=0·028), bulbar weakness (11 [44%] of 25 vs two [7%] of 30; p=0·028), bowel or bladder dysfunction (14 [56%] of 25 vs seven [23%] of 30; p=0·040), cardiovascular instability (nine [36%] of 25 vs one [3%] of 30; p=0·028), and were more likely to require intensive care unit admission (13 [52%] of 25 vs 5 [17%] of 30; p=0·028). On MRI, most children who were enterovirus positive showed brainstem pontine lesions (14 [61%] of 23), while other MRI parameters did not correlate with enterovirus status. Median EDSS of enterovirus positive (EV+) and enterovirus negative (EV–) groups was significantly different at all timepoints: baseline (EDSS 8·5, IQR 4·1–9·5 vs EDSS 4·0, IQR 3·0–6·0; p=0·0067), 3 months (EDSS 4·0, IQR 3·0–7·4 vs EDSS 3·0, IQR 1·5–4·3; p=0·0067), 6 months (EDSS 3·5, IQR 3·0–7·0 vs EDSS 3·0, IQR 1·0–4·0; p=0·029), and 12 months (EDSS 3·0, IQR 3·0–6·9 vs EDSS 2·5 IQR 0·3–3·0; p=0·0067). Kaplan-Meier survival analysis of a subgroup of patients showed significantly poorer motor recovery among children who tested positive for enterovirus than for those who tested negative (p=0·037). Interpretation Detection of enterovirus in specimens from non-sterile sites at presentation correlated with more severe acute motor weakness, worse overall outcomes and poorer trajectory for motor recovery. These results have implications for rehabilitation planning as well as counselling of families of children with these disorders. The findings of this study support the need for early testing for enterovirus in non-CNS sites in all cases of AFM. Funding None.

Genetically determined leukoencephalopathies comprise a group of rare inherited white matter disorders. The majority are progressive diseases resulting in early death. We performed a cross-sectional pilot study including 55 parents from 36 families to assess the level of stress experienced by parents of patients with genetically determined leukoencephalopathies, aged 1 month to 12 years. Thirty-four mothers and 21 fathers completed the Parenting Stress Index–4th Edition. One demographic questionnaire was completed per family. Detailed clinical data was gathered on all patients. Statistical analysis was performed with total stress percentile score as the primary outcome. Mothers and fathers had significantly higher stress levels compared with the normative sample; 20% of parents had high levels of stress whereas 11% had clinically significant levels of stress. Mothers and fathers had comparable total stress percentile scores. We identified pediatric behavioral difficulties and gross motor function to be factors influencing stress in mothers. Our study is the first to examine parental stress in this population and highlights the need for parental support early in the disease course. In this pilot study, we demonstrated that using the Parenting Stress Index–4th Edition to assess stress levels in parents of patients with genetically determined leukoencephalopathies is feasible, leads to valuable and actionable results, and should be used in larger, prospective studies.

International audience; PURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved.METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types of SOX5 alterations. Functional consequences of selected substitutions were investigated.RESULTS: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated.CONCLUSIONS:This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.

To explore the relationships between clinical-radiological features and surgical outcomes in subjects with interhemispheric cysts (IHC) and corpus callosum anomalies.We reviewed the clinico-radiological and neurosurgical data of 38 patients surgically treated with endoscopic fenestration, shunting, or combined approaches from 2000 to 2018 (24 males, median age 9 years). Pre- and postoperative changes in IHC volume were calculated. Outcome assessment was based on clinico-radiological data. Group comparisons were performed using χMedian age at first surgery was 4 months (mean follow-up 8.3 years). Eighteen individuals (47.3%) required 1 intervention due to IHC regrowth and/or shunt malfunction. Larger preoperative IHC volume (P = .008) and younger age at surgery (P = .016) were associated with cyst regrowth. At last follow-up, mean cystic volume was 307.8 cmEndoscopic fenestration and shunting approaches are both effective but often require multiple procedures especially in younger patients. Larger IHC are more frequently complicated by cyst regrowth after surgery.

Parents of children with genetically determined leukoencephalopathies play a major role in their children's health care. We sought to gain a better understanding of their experience with the public health care system in Quebec, Canada, to obtain suggestions for improving their services, and to identify modifiable factors to improve their quality of life. We conducted interviews with 13 parents. Data was analyzed thematically. Five themes were identified: challenges of the diagnostic odyssey, limited access to services, excessive parental responsibilities, positive relationships with health care professionals as a facilitator of care, and benefits of a specialized leukodystrophy clinic. Parents felt like waiting for the diagnosis was extremely stressful, and they expressed their need for transparency during this period. They identified multiple gaps and barriers in the health care system, which burdened them with many responsibilities. Parents emphasized the importance of a positive relationship with their child's health care professionals. They also felt grateful for being followed at a specialized clinic as it improved the quality of care received.

Parents of children with genetically determined leukoencephalopathies play a major role in their children's health care. Because of the COVID-19 pandemic, many health care services were suspended, delayed or delivered remotely with telemedicine. We sought to explore the experience of parents of children with genetically determined leukoencephalopathies during the pandemic given the adapted health care services. We conducted semistructured interviews with 13 parents of 13 affected children. Three main themes were identified using thematic analysis: perceived impact of COVID-19 on health care services, benefits and challenges of telemedicine, and expectations of health care after the pandemic. Parents perceived a loss/delay in health care services while having a positive response to telemedicine. Parents wished telemedicine would remain in their care after the pandemic. This is the first study assessing the impact of COVID-19 on health care services in this population. Our results suggest that parents experience a higher level of stress owing to the shortage of services and the children's vulnerability.

Myelin regeneration in the human central nervous system relies on progenitor cells within the tissue parenchyma, with possible contribution from previously myelinating oligodendrocytes (OLs). In multiple sclerosis, a demyelinating disorder, variables affecting remyelination efficiency include age, severity of initial injury, and progenitor cell properties. Our aim was to investigate the effects of age and differentiation on the myelination potential of human OL lineage cells.We derived viable primary OL lineage cells from surgical resections of pediatric and adult brain tissue. Ensheathment capacity using nanofiber assays and transcriptomic profiles from RNA sequencing were compared between A2B5+ antibody-selected progenitors and mature OLs (non-selected cells).We demonstrate that pediatric progenitor and mature cells ensheathed nanofibers more robustly than did adult progenitor and mature cells, respectively. Within both age groups, the percentage of fibers ensheathed and ensheathment length per fiber were greater for A2B5+ progenitors. Gene expression of OL progenitor markers PDGFRA and PTPRZ1 were higher in A2B5+ versus A2B5- cells and in pediatric A2B5+ versus adult A2B5+ cells. The p38 MAP kinases and actin cytoskeleton-associated pathways were upregulated in pediatric cells; both have been shown to regulate OL process outgrowth. Significant upregulation of "cell senescence" genes was detected in pediatric samples; this could reflect their role in development and the increased susceptibility of pediatric OLs to activating cell death responses to stress.Our findings identify specific biological pathways relevant to myelination that are differentially enriched in human pediatric and adult OL lineage cells and suggest potential targets for remyelination enhancing therapies. ANN NEUROL 2022;91:178-191.

The term spinocerebellar ataxia encompasses a heterogeneous group of neurodegenerative disorders due to pathogenic variants in more than 100 genes, underlying 2 major groups of ataxia: autosomal dominant cerebellar ataxias (ADCA, also known as spinocerebellar ataxias [SCAs]) due to heterozygous variants or polyglutamine triplet expansions leading to adult-onset ataxia, and autosomal recessive spinocerebellar ataxias (ARCAs, also known as SCARs) due to biallelic variants, usually resulting in more severe and earlier-onset cerebellar ataxia. Certain ataxia genes, including SPTBN2 which encodes β-III spectrin, are responsible for both SCA and SCAR, depending on whether the pathogenic variant occurs in a monoallelic or biallelic state, respectively. Accordingly, 2 major phenotypes have been linked to SPTBN2: pathogenic heterozygous in-frame deletions and missense variants result in an adult-onset, slowly progressive ADCA (SCA5) through a dominant negative effect, whereas biallelic loss-of-function variants cause SCAR14, an allelic disorder characterized by infantile-onset cerebellar ataxia and cognitive impairment. Of note, 2 heterozygous missense variants (c.1438C>T, p.R480 W; c.1309C>G, p.R437G), both lying in the second spectrin repeat of SPTBN2, have been linked to infantile-onset cerebellar ataxia, similar to SCAR14. Here, we report a novel de novo heterozygous pathogenic missense variant (c.1310G>A) in SPTBN2 in a child with infantile-onset cerebellar ataxia and mild cognitive impairment. This variant affects the same R437 residue of the second spectrin repeat but results in a different amino acid change (p.R437Q). We review previously reported cases and discuss possible pathomechanisms responsible for the early-onset cerebellar phenotype due to disease-causing variants in the second spectrin repeat.

Mutations in DYNC1H1 have been shown to cause spinal muscular atrophy lower extremity predominant type 1 (SMALED1), an autosomal dominant genetic neuromuscular disorder characterized by degeneration of spinal cord motor neurons resulting in muscle weakness. Here, we describe monozygotic twins, one with a more severe upper motor neuron phenotype as a result of a suspected perinatal hypoxic-ischemic event and the other presenting a typical lower motor neuron phenotype. Using exome sequencing, we identified the novel de novo variant c.752G>T; p.Arg251Leu in DYNC1H1. We thereby add this variant to the growing list of mutations in DYNC1H1 that cause SMALED1.

Mutations in DYNC1H1 have been shown to cause spinal muscular atrophy lower extremity predominant type 1 (SMALED1), an autosomal dominant genetic neuromuscular disorder characterized by degeneration of spinal cord motor neurons resulting in muscle weakness. Here, we describe monozygotic twins, one with a more severe upper motor neuron phenotype as a result of a suspected perinatal hypoxic-ischemic event and the other presenting a typical lower motor neuron phenotype. Using exome sequencing, we identified the novel de novo variant c.752G>T; p.Arg251Leu in DYNC1H1 . We thereby add this variant to the growing list of mutations in DYNC1H1 that cause SMALED1.

Data on fetal MRI in L1 syndrome are scarce with relevant implications for parental counseling and surgical planning. We identified two fetal MR imaging patterns in 10 fetuses harboring L1CAM mutations: the first, observed in 9 fetuses was characterized by callosal anomalies, diencephalosynapsis, and a distinct brainstem malformation with diencephalic–mesencephalic junction dysplasia and brainstem kinking. Cerebellar vermis hypoplasia, aqueductal stenosis, obstructive hydrocephalus, and pontine hypoplasia were variably associated. The second pattern observed in one fetus was characterized by callosal dysgenesis, reduced white matter, and pontine hypoplasia. The identification of these features should alert clinicians to offer a prenatal L1CAM testing.

A 17-year-old boy was diagnosed with congenital lipomatous overgrowth with vascular, epidermal, skeletal, and spinal anomalies (CLOVES) syndrome,1 mainly affecting his right face, brain, and trunk (MIM#612918) (figure, A–C). Brain MRI revealed right hemimegalencephaly with extensive temporo-parieto-occipital cortical dysplasia (figure 1, D1-4). He developed neonatal drug-resistant seizures requiring right hemispherectomy at 15 months. He has left hemiparesis and intellectual disability. CLOVES syndrome is a segmental overgrowth syndrome associated with somatic hyperactivating mutations in PIK3CA , belonging to the mammalian target of rapamycin signaling pathway.2 Genetic testing on buccal swab revealed a pathogenic somatic missense mutation in PIK3CA (NM_006218.4:c.1624G>A, p.Glu542Lys) at an alternate allele frequency of 4.5%, which was absent in blood.

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.

Development of the central nervous system (CNS) is a complex, dynamic process that involves a precisely orchestrated sequence of genetic, environmental, biochemical, and physical factors from early embryonic stages to postnatal life. Duringthe past decade, great strides have been made to unravel mechanisms underlying human CNS development through the employment of modern genetic techniques and experimental approaches. In this chapter, we review the current knowledge regarding the main developmental processes and signaling mechanisms of (i) neurogenesis, (ii) neuronal migration, and (iii) axon guidance. We discuss mechanisms related to neural stem cells proliferation, migration, terminal translocation of neuronal progenitors, and axon guidance and pathfinding. For each section, we also provide a comprehensive overview of the underlying regulatory processes, including transcriptional, posttranscriptional, and epigenetic factors, and a myriad of signaling pathways that are pivotal to determine the fate of neuronal progenitors and newly formed migrating neurons. We further highlight how impairment of this complex regulating system, such as mutations in its core components, may cause cortical malformation, epilepsy, intellectual disability, and autism in humans. A thorough understanding of normal human CNS development is thus crucial to decipher mechanisms responsible for neurodevelopmental disorders and in turn guide the development of effective and targeted therapeutic strategies.

Myelin destruction and oligodendrocyte (OL) death consequent to metabolic stress is a feature of CNS disorders across the age spectrum. Using cells derived from surgically resected tissue, we demonstrate that young (, Milton Fernandes et al. combine single cell RNA-sequencing and functional assays to show that human oligodendrocytes exhibit an age-dependent resistance to apoptosis. Their findings have important implications for the pathology and treatment of myelination disorders like multiple sclerosis.

Objective Recently identified mutations of the axon guidance molecule receptor gene, DCC, present an opportunity to investigate, in living human brain, mechanisms affecting neural connectivity and the basis of mirror movements, involuntary contralateral responses that mirror voluntary unilateral actions. We hypothesized that haploinsufficient DCC+/- mutation carriers with mirror movements would exhibit decreased DCC mRNA expression, a functional ipsilateral corticospinal tract, greater "mirroring" motor representations, and reduced interhemispheric inhibition. DCC+/- mutation carriers without mirror movements might exhibit some of these features. Methods The participants (n = 52) included 13 DCC+/- mutation carriers with mirror movements, 7 DCC+/- mutation carriers without mirror movements, 13 relatives without the mutation or mirror movements, and 19 unrelated healthy volunteers. The multimodal approach comprised quantitative real time polymerase chain reaction, transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI) under resting and task conditions, and measures of white matter integrity. Results Mirror movements were associated with reduced DCC mRNA expression, increased ipsilateral TMS-induced motor evoked potentials, increased fMRI responses in the mirroring M1 and cerebellum, and markedly reduced interhemispheric inhibition. The DCC+/- mutation, irrespective of mirror movements, was associated with reduced functional connectivity and white matter integrity. Interpretation Diverse connectivity abnormalities were identified in mutation carriers with and without mirror movements, but corticospinal effects and decreased peripheral DCC mRNA appeared driven by the mirror movement phenotype. ANN NEUROL 2019;85:433-442.

Hemiconvulsion‐Hemiplegia‐Epilepsy initially involves an infantile presentation of febrile focal motor status epilepticus, with subsequent hemiplegia of the initially affected side. Months to years later, affected children go on to develop a chronic epilepsy with recurrent focal seizures which are often refractory to treatment. This uncommon paediatric epilepsy syndrome is poorly understood, with only a very small minority of cases associated with an underlying genetic or metabolic abnormality. We present a four‐year‐old girl with genetic cobalamin C deficiency who had a dramatic presentation with Hemiconvulsion‐Hemiplegia‐Epilepsy. She had febrile focal status epilepticus, with right hemiconvulsive seizures for nearly 10 hours, ultimately requiring a midazolam infusion. Over subsequent days, she developed progressively worsening cerebral oedema, leading to herniation and requiring a craniectomy to relieve pressure. This girl's presentation is the first association of cobalamin deficiency with hemiconvulsion‐hemiplegia‐epilepsy; and illustrates the importance of considering this entity when patients with this metabolic disorder present with acute deterioration. More importantly, the case also raises the possibility that derangements of cobalamin metabolism could be a contributing factor in cases of hemiconvulsion‐hemiplegia‐epilepsy, as well as febrile seizures in general.

Aim Neurodevelopmental outcomes in children with congenital cerebellar malformations (CCMs) remain poorly defined. We aimed to assess whether specific neuroimaging features in CCM patients correlate with neurodevelopmental outcomes. Method Hospital records and neuroimaging of 67 children with CCMs were systematically reviewed. Logistic regression analyses were used to assess associations between specific imaging features and neurodevelopmental outcomes. Results CCM categories were distributed as follows: 28 percent isolated vermis hypoplasia (n=19), 28 percent global cerebellar hypoplasia (n=19), 15 percent Dandy-Walker malformation (n=10), 13 percent pontocerebellar hypoplasia (PCH, n=9), 9 percent molar tooth malformation (n=6), 3 percent rhombencephalosynapsis (n=2), and 3 percent unilateral cerebellar malformation (n=2). Overall, 85 percent (55/65) of the cohort had global developmental delay (GDD). Intellectual disability was present in 61 percent (27/43) and autism spectrum disorder (ASD) in 12 percent (6/52). Adjusting for supratentorial malformations and presence of genetic findings, severe GDD was associated with cerebellar hypoplasia (p=0.049) and PCH (p=0.030), whereas children with vermis hypoplasia were less likely to have severe GDD (p=0.003). Presence of supratentorial abnormalities was not significantly associated with worse neurodevelopmental outcome but was associated with epilepsy. Interpretation Children with CCMs have high prevalence of neurodevelopmental deficits. Specific features on imaging can aid prognostication and establish early intervention strategies. What this paper adds Atypical long-term neurodevelopmental outcome is very common in patients with congenital cerebellar malformations (CCMs). Involvement of the brainstem and cerebellar hemispheres predicts more severe neurodevelopmental disability. Most patients with vermis hypoplasia have language delay but are verbal. Supratentorial abnormalities are not significantly associated with worse neurodevelopmental outcome but are associated with epilepsy. Comorbidities are common in CCMs, especially ophthalmological issues in cerebellar hypoplasia and sensorineural hearing loss in pontocerebellar hypoplasia.

The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate whether this occurs in humans, we measured (1) anatomical connectivity between the substantia nigra/ventral tegmental area (SN/VTA) and forebrain targets, (2) striatal and cortical volumes, and (3) putatively associated traits and behaviors. To assess translatability, morphometric data were also collected inDcc-haploinsufficient mice. The human volunteers were 20DCC+/−mutation carriers, 16DCC+/+relatives, and 20DCC+/+unrelated healthy volunteers (UHVs; 28 females). The mice were 11Dcc+/−and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the humanDCC+/−carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum [DCC+/+:p= 0.0005,r(effect size) = 0.60; UHV:p= 0.0029,r= 0.48] and ventral medial prefrontal cortex (DCC+/+:p= 0.0031,r= 0.53; UHV:p= 0.034,r= 0.35); (2) lower novelty-seeking scores (DCC+/+:p= 0.034,d= 0.82; UHV:p= 0.019,d= 0.84); and (3) reduced striatal volume (DCC+/+:p= 0.0009,d= 1.37; UHV:p= 0.0054,d= 0.93). Striatal volumetric reductions were also present inDcc+/−mice, and these were seen during adolescence (p= 0.0058,d= 1.09) and adulthood (p= 0.003,d= 1.26). Together these findings provide the first evidence in humans that an axon guidance gene is involved in the formation of mesocorticolimbic circuitry and related behavioral traits, providing mechanisms through whichDCCmutations might affect susceptibility to diverse neuropsychiatric disorders.SIGNIFICANCE STATEMENTOpportunities to study the effects of axon guidance molecules on human brain development have been rare. Here, the identification of a large four-generational family that carries a mutation to the axon guidance molecule receptor gene,DCC, enabled us to demonstrate effects on mesocorticolimbic anatomical connectivity, striatal volumes, and personality traits. Reductions in striatal volumes were replicated inDCC-haploinsufficient mice. Together, these processes might influence mesocorticolimbic function and susceptibility to diverse neuropsychiatric disorders.

PCDH12 is a member of the non-clustered protocadherins that mediate cell-cell adhesion, playing crucial roles in many biological processes. Among these, PCDH12 promotes cell-cell interactions at inter-endothelial junctions, exerting essential functions in vascular homeostasis and angiogenesis. However, its exact role in eye vascular and brain development is not completely understood. To date, biallelic loss of function variants in PCDH12 have been associated with a neurodevelopmental disorder characterized by the typical neuroradiological findings of diencephalic-mesencephalic junction dysplasia and intracranial calcifications, whereas heterozygous variants have been recently linked to isolated brain calcifications in absence of cognitive impairment or other brain malformations. Recently, the phenotypic spectrum associated with PCDH12 deficiency has been expanded including cerebellar and eye abnormalities. Here, we report two female siblings harboring a novel frameshift homozygous variant (c.2169delT, p.(Val724TyrfsTer8)) in PCDH12. In addition to the typical diencephalic-mesencephalic junction dysplasia, brain MRI showed dysmorphic basal ganglia and thalamus that were reminiscent of a tubulin-like phenotype, mild cerebellar vermis hypoplasia and extensive prominence of perivascular spaces in both siblings. The oldest sister developed profound and progressive monocular visual loss and the eye exam revealed exudative vitreoretinopathy. Similar but milder eye changes were also noted in her younger sister. In summary, our report expands the clinical (brain and ocular) spectrum of PCDH12-related disorders and adds a further line of evidence underscoring the important role of PCDH12 in retinal vascular and brain development.

We retrospectively reviewed the clinical and radiologic characteristics of 17 individuals with septo-optic dysplasia (SOD) and attempted to identify correlations between imaging findings, clinical features, and neurodevelopmental outcome. Surprisingly, only 1 (6%) individual was classified as classic SOD (with septum pellucidum/corpus callosum dysgenesis), 3 (18%) as SOD-like (with normal septum pellucidum/corpus callosum) and the majority, 13 (76%), as SOD-plus (with cortical brain malformation). Cortical abnormalities included schizencephaly, polymicrogyria, and gray matter heterotopias. All individuals had optic nerve hypoplasia, 11 (65%) had endocrinologic deficits, and 13 (76%) had abnormal cerebral midlines. Seven individuals (41%) had all 3 features. Neurodevelopmental outcome was abnormal in 13 (78%), ranging from mild to severe developmental delay. Individuals with SOD-plus did not have more severe neurologic deficits than individuals with classic or SOD-like subgroups. Thus, SOD is clinically and radiologically heterogeneous, and cortical abnormalities are very common. Neurodevelopmental deficits are very prevalent, and of wide-ranging severity.