Aim
To identify subtypes of developmental coordination disorder (DCD) in children.
Method
Children with DCD diagnosed through comprehensive evaluation at Robert‐Debré Children's University Hospital ...(Paris, France) were consecutively enrolled from February 2017 to March 2020. We performed an unsupervised hierarchical clustering based on principal component analysis using a large set of variables encompassing cognitive, motor, and visuospatial scores (Wechsler Intelligence Scale for Children, Fifth Edition; Developmental Neuropsychological Assessment, Second Edition; Movement Assessment Battery for Children, Second Edition).
Results
One hundred and sixty‐four children with DCD were enrolled (median age 10 years 3 months; male:female ratio 5.56:1). We identified distinct subgroups with mixed visuospatial and gestural disorders, or with pure gestural disorders that predominantly impaired either speed or precision. Associated neurodevelopmental disorders, such as attention‐deficit/hyperactivity disorder, did not influence the results of the clustering. Importantly, we identified a subgroup of children with marked visuospatial impairment with the lowest scores in almost all of the evaluated domains, and the poorest school performance.
Interpretation
The classification of DCD into distinct subgroups could be indicative of prognosis and provide critical information to guide patient management, taking into account the child's neuropsychological profile. Beyond this clinical interest, our findings also provide a relevant framework with homogeneous subgroups of patients for research on the pathogenesis of DCD.
What this paper adds
Unsupervised hierarchical clustering identified four subgroups of children with developmental coordination disorder.
Two subgroups had combined visuospatial/gestural difficulties, and two had pure gestural disorders.
Severe visuospatial impairment was associated with poor performance in most domains including school.
Difficulties in the gestural‐only clusters were predominantly either gestural precision or speed.
What this paper adds
Unsupervised hierarchical clustering identified four subgroups of children with developmental coordination disorder.
Two subgroups had combined visuospatial/gestural difficulties, and two had pure gestural disorders.
Severe visuospatial impairment was associated with poor performance in most domains including school.
Difficulties in the gestural‐only clusters were predominantly either gestural precision or speed.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
IFIH1 gain‐of‐function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten ...syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In fetal alcohol spectrum disorders (FASD), brain growth deficiency is a hallmark of subjects both with fetal alcohol syndrome (FAS) and with non‐syndromic FASD (NS‐FASD, i.e., those without specific ...diagnostic features). However, although the cerebellum was suggested to be more severely undersized than the rest of the brain, it has not yet been given a specific place in the FASD diagnostic criteria where neuroanatomical features still count for little if anything in diagnostic specificity. We applied a combination of cerebellar segmentation tools on a 1.5 T 3DT1 brain MRI dataset from a monocentric population of 89 FASD (52 FAS, 37 NS‐FASD) and 126 typically developing controls (6–20 years old), providing 8 volumes: cerebellum, vermis and 3 lobes (anterior, posterior, inferior), plus total brain volume. After adjustment of confounders, the allometric scaling relationship between these cerebellar volumes (Vi) and the total brain or cerebellum volume (Vt) was fitted (Vi = bVta), and the effect of group (FAS, control) on allometric scaling was evaluated. We then estimated for each cerebellar volume in the FAS population the deviation from the typical scaling (vDTS) learned in the controls. Lastly, we trained and tested two classifiers to discriminate FAS from controls, one based on the total cerebellum vDTS only, the other based on all the cerebellar vDTS, comparing their performance both in the FAS and the NS‐FASD group. Allometric scaling was significantly different between FAS and control group for all the cerebellar volumes (p < .001). We confirmed the excess of total cerebellum volume deficit (vDTS = −10.6%) and revealed an antero‐inferior‐posterior gradient of volumetric undersizing in the hemispheres (−12.4%, 1.1%, 2.0%, respectively) and the vermis (−16.7%, −9.2%, −8.6%, repectively). The classifier based on the intracerebellar gradient of vDTS performed more efficiently than the one based on total cerebellum vDTS only (AUC = 92% vs. 82%, p = .001). Setting a high probability threshold for >95% specificity of the classifiers, the gradient‐based classifier identified 35% of the NS‐FASD to have a FAS cerebellar phenotype, compared to 11% with the cerebellum‐only classifier (pFISHER = 0.027). In a large series of FASD, this study details the volumetric undersizing within the cerebellum at the lobar and vermian level using allometric scaling, revealing an anterior‐inferior‐posterior gradient of vulnerability to prenatal alcohol exposure. It also strongly suggests that this intracerebellar gradient of volumetric undersizing may be a reliable neuroanatomical signature of FAS that could be used to improve the specificity of the diagnosis of NS‐FASD.
In fetal alcohol syndrome (FAS), the cerebellum is smaller than expected for brain size, and within the cerebellum follows an anterior‐posterior‐inferior gradient of severity.
A classifier including this cerebellar gradient efficiently discriminating FAS from controls categorizes one third of the non syndromic fetal alcohol spectrum disorder subjects with a FAS‐like cerebellar pattern.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Central nervous system (CNS) dural arteriovenous fistulas (DAVF) have been reported in PTEN‐related hamartoma tumor syndrome (PHTS). However, PHTS‐associated DAVF remain an underexplored field of the ...PHTS clinical landscape. Here, we studied cases with a PTEN pathogenic variant identified between 2007 and 2020 in our laboratory (n = 58), and for whom brain imaging was available. Two patients had DAVF (2/58, 3.4%), both presenting at advanced stages: a 34‐year‐old man with a left lateral sinus DAVF at immediate risk of hemorrhage, and a 21‐year‐old woman with acute intracranial hypertension due to a torcular DAVF. Interestingly, not all patients had 3D TOF/MRA, the optimal sequences to detect DAVF. Early diagnosis of DAVF can be lifesaving, and is easier to treat compared to developed, proliferative, or complex lesions. As a result, one should consider brain MRI with 3D TOF/MRA in PHTS patients at genetic diagnosis, with subsequent surveillance on a case‐by‐case basis.
Among a series of patients with PHTS (n = 58), two patients had dural arteriovenous fistulas, both presenting at advanced stages. Early diagnosis facilitates treatment of these rare, life‐threatening lesions and can be lifesaving. Brain MRI with 3D TOF/MRA should be considered in PHTS patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background and purpose
Diagnostic criteria for adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony‐stimulating factor 1 receptor (CSF1R) mutation have ...recently been proposed. Our objective was to assess their accuracy in an independent multicenter cohort.
Methods
We evaluated the sensitivity and specificity of the diagnostic criteria for ALSP (including the “probable” and “possible” definitions) in a national cohort of 22 patients with CSF1R mutation, and 59 patients with an alternative diagnosis of adult onset inherited leukoencephalopathy.
Results
Overall, the sensitivity of the diagnostic criteria for ALSP was 82%, including nine of 22 patients diagnosed as probable and nine of 22 diagnosed as possible. Twenty of the 59 CSF1R mutation‐negative leukoencephalopathies fulfilled the diagnostic criteria, leading to a specificity of 66%.
Conclusions
Diagnostic criteria for ALSP have an overall limited sensitivity along with a modest specificity. We suggest that in patients suspected of genetic leukoencephalopathy, a comprehensive magnetic resonance imaging pattern‐based approach is warranted, together with white matter gene panel or whole exome sequencing.
Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is due to heterozygous CSF1R mutations. It is increasingly recognized as a major cause of inherited leukoencephalopathies in adulthood. Our study assessed the sensitivity and specificity of diagnostic criteria for ALSP and suggests that they may be misleading. Instead, we propose that every patient with an unexplained rapidly evolving leukoencephalopathy should be tested for a CSF1R mutation, as a potential therapy (allogenic hematopoietic stem cell transplantation) exists.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective
SLC13A3 encodes the plasma membrane Na+/dicarboxylate cotransporter 3, which imports inside the cell 4 to 6 carbon dicarboxylates as well as N‐acetylaspartate (NAA). SLC13A3 is mainly ...expressed in kidney, in astrocytes, and in the choroid plexus. We describe two unrelated patients presenting with acute, reversible (and recurrent in one) neurological deterioration during a febrile illness. Both patients exhibited a reversible leukoencephalopathy and a urinary excretion of α‐ketoglutarate (αKG) that was markedly increased and persisted over time. In one patient, increased concentrations of cerebrospinal fluid NAA and dicarboxylates (including αKG) were observed. Extensive workup was unsuccessful, and a genetic cause was suspected.
Methods
Whole exome sequencing (WES) was performed. Our teams were connected through GeneMatcher.
Results
WES analysis revealed variants in SLC13A3. A homozygous missense mutation (p.Ala254Asp) was found in the first patient. The second patient was heterozygous for another missense mutation (p.Gly548Ser) and an intronic mutation affecting splicing as demonstrated by reverse transcriptase polymerase chain reaction performed in muscle tissue (c.1016 + 3A > G). Mutations and segregation were confirmed by Sanger sequencing. Functional studies performed on HEK293T cells transiently transfected with wild‐type and mutant SLC13A3 indicated that the missense mutations caused a marked reduction in the capacity to transport αKG, succinate, and NAA.
Interpretation
SLC13A3 deficiency causes acute and reversible leukoencephalopathy with marked accumulation of αKG. Urine organic acids (especially αKG and NAA) and SLC13A3 mutations should be screened in patients presenting with unexplained reversible leukoencephalopathy, for which SLC13A3 deficiency is a novel differential diagnosis. ANN NEUROL 2019;85:385–395.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Glucose transporter type 1 (GLUT1) deficiency syndrome (GLUT1‐DS) leads to a wide range of neurological symptoms. Ketogenic diets are very efficient to control epilepsy and movement disorders. We ...tested a novel simple and rapid blood test in 30 patients with GLUT1‐DS with predominant movement disorders, 18 patients with movement disorders attributed to other genetic defects, and 346 healthy controls. We detected significantly reduced GLUT1 expression only on red blood cells from patients with GLUT1‐DS (23 patients; 78%), including patients with inconclusive genetic analysis. This test opens perspectives for the screening of GLUT1‐DS in children and adults with cognitive impairment, movement disorder, or epilepsy. Ann Neurol 2017;82:133–138
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Achaete-Scute Family basic-helix-loop-helix (bHLH) Transcription Factor 1 (ASCL1) is a proneural transcription factor involved in neuron development in the central and peripheral nervous system. ...While initially suspected to contribute to congenital central hypoventilation syndrome-1 (CCHS) with or without Hirschsprung disease (HSCR) in three individuals, its implication was ruled out by the presence, in one of the individuals, of a Paired-like homeobox 2B (PHOX2B) heterozygous polyalanine expansion variant, known to cause CCHS. We report two additional unrelated individuals sharing the same sporadic ASCL1 p.(Glu127Lys) missense variant in the bHLH domain and a common phenotype with short-segment HSCR, signs of dysautonomia, and developmental delay. One has also mild CCHS without polyalanine expansion in PHOX2B, compatible with the diagnosis of Haddad syndrome. Furthermore, missense variants with homologous position in the same bHLH domain in other genes are known to cause human diseases. The description of additional individuals carrying the same variant and similar phenotype, as well as targeted functional studies, would be interesting to further evaluate the role of ASCL1 in neurocristopathies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Pelizaeus‐Merzbacher disease (PMD) is a fatal hypomyelinating disorder characterized by early impairment of motor development, nystagmus, choreoathetotic movements, ataxia and progressive spasticity. ...PMD is caused by variations in the proteolipid protein gene PLP1, which encodes the two major myelin proteins of the central nervous system, PLP and its spliced isoform DM20, in oligodendrocytes. Large duplications including the entire PLP1 gene are the most frequent causative mutation leading to the classical form of PMD. The Plp1 overexpressing mouse model (PLP‐tg66/66) develops a phenotype very similar to human PMD, with early and severe motor dysfunction and a dramatic decrease in lifespan. The sequence of cellular events that cause neurodegeneration and ultimately death is poorly understood. In this work, we analyzed patient‐derived fibroblasts and spinal cords of the PLP‐tg66/66 mouse model, and identified redox imbalance, with altered antioxidant defense and oxidative damage to several enzymes involved in ATP production, such as glycolytic enzymes, creatine kinase and mitochondrial proteins from the Krebs cycle and oxidative phosphorylation. We also evidenced malfunction of the mitochondria compartment with increased ROS production and depolarization in PMD patient's fibroblasts, which was prevented by the antioxidant N‐acetyl‐cysteine. Finally, we uncovered an impairment of mitochondrial dynamics in patient's fibroblasts which may help explain the ultrastructural abnormalities of mitochondria morphology detected in spinal cords from PLP‐tg66/66 mice. Altogether, these results underscore the link between redox and metabolic homeostasis in myelin diseases, provide insight into the pathophysiology of PMD, and may bear implications for tailored pharmacological intervention.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Mutations in MLC1 cause megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare form of leukodystrophy characterized by macrocephaly, epilepsy, spasticity, and slow mental ...deterioration. Genetic studies of MLC are lacking from many parts of the world, especially in Sub-Saharan Africa. Genomic DNA was extracted for 67 leukodystrophic patients from 43 Sudanese families. Mutations were screened using the NGS panel testing 139 leukodystrophies and leukoencephalopathies causing genes (NextSeq500 Illumina). Five homozygous MLC1 variants were discovered in seven patients from five distinct families, including three consanguineous families from the same region of Sudan. Three variants were missense (c.971 T > G, p.Ile324Ser; c.344 T > C, p.Phe115Ser; and c.881 C > T, p.Pro294Leu), one duplication (c.831_838dupATATCTGT, p.Ser280Tyrfs*8), and one synonymous/splicing-site mutation (c.762 C > T, p.Ser254). The segregation pattern was consistent with autosomal recessive inheritance. The clinical presentation and brain MRI of the seven affected patients were consistent with the diagnosis of MLC1. Due to the high frequency of distinct MLC1 mutations found in our leukodystrophic Sudanese families, we analyzed the coding sequence of MLC1 gene in 124 individuals from the Sudanese genome project in comparison with the 1000-genome project. We found that Sudan has the highest proportion of deleterious variants in MLC1 gene compared with other populations from the 1000-genome project.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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