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.
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.
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.
Background and purpose
Spinal muscular atrophy (SMA) is caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and/or mutations in the SMN1 gene. Risdiplam is an orally ...administered molecule that modifies SMN2 pre‐mRNA splicing to increase functional SMN protein.
Methods
SUNFISH Part 1 was a dose‐finding study conducted in 51 individuals with types 2 and 3 SMA aged 2–25 years. A dose‐escalation method was used to identify the appropriate dose for the subsequent pivotal Part 2. Individuals were randomized (2:1) to risdiplam or placebo at escalating dose levels for a minimum 12‐week, double‐blind, placebo‐controlled period, followed by treatment for 24 months. The dose selection for Part 2 was based on safety, tolerability, pharmacokinetic, and pharmacodynamic data. Exploratory efficacy was also measured.
Results
There was no difference in safety findings for all assessed dose levels. A dose‐dependent increase in blood SMN protein was observed; a median twofold increase was obtained within 4 weeks of treatment initiation at the highest dose level. The increase in SMN protein was sustained over 24 months of treatment. Exploratory efficacy showed improvement or stabilization in motor function. The pivotal dose selected for Part 2 was 5 mg for patients with a body weight ≥20 kg or 0.25 mg/kg for patients with a body weight <20 kg.
Conclusions
SUNFISH Part 1 demonstrated a twofold increase in SMN protein after treatment with risdiplam. The observed safety profile supported the initiation of the pivotal Part 2 study. The long‐term efficacy and safety of risdiplam are being assessed with ongoing treatment.
SUNFISH Part 1 demonstrated a safety profile and pharmacodynamic effect sufficient to support further study of risdiplam treatment in individuals with types 2 and 3 SMA. The long‐term efficacy and safety of risdiplam are being assessed with ongoing treatment.
The aim of the study was to redefine the phenotype of Allan–Herndon–Dudley syndrome (AHDS), which is caused by mutations in the SLC16A2 gene that encodes the brain transporter of thyroid hormones. ...Clinical phenotypes, brain imaging, thyroid hormone profiles, and genetic data were compared to the existing literature. Twenty‐four males aged 11 months to 29 years had a mutation in SLC16A2, including 12 novel mutations and five previously described mutations. Sixteen patients presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications. This study extends the phenotypic spectrum of AHDS to a mild intellectual disability with hypotonia. Developmental delay, hypotonia, hypomyelination, and thyroid hormone profile help to diagnose patients. Clinical course depends on initial severity, with stable acquisition after infancy; this may be adversely affected by neuro‐orthopaedic, pulmonary, and epileptic complications.
What this paper adds
Mild intellectual disability is associated with SLC16A2 mutations.
A thyroid hormone profile with a free T3/T4 ratio higher than 0.75 can help diagnose patients.
Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders.
Axial hypotonia is a consistent feature of Allan–Herndon–Dudley syndrome and leads to specific complications.
What this paper adds
Mild intellectual disability is associated with SLC16A2 mutations.
A thyroid hormone profile with a free T3/T4 ratio higher than 0.75 can help diagnose patients.
Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders.
Axial hypotonia is a consistent feature of Allan–Herndon–Dudley syndrome and leads to specific complications.
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.
Aim
To identify easily accessible neuroanatomical abnormalities useful for diagnosing fetal alcohol spectrum disorders (FASD) in fetal alcohol syndrome (FAS) but more importantly for the ...probabilistic diagnosis of non‐syndromic forms (NS‐FASD).
Method
We retrospectively collected monocentric data from 52 individuals with FAS, 37 with NS‐FASD, and 94 paired typically developing individuals (6–20 years, 99 males, 84 females). On brain T1‐weighted magnetic resonance imaging, we measured brain size, corpus callosum length and thicknesses, vermis height, then evaluated vermis foliation (Likert scale). For each parameter, we established variations with age and brain size in comparison individuals (growth and scaling charts), then identified participants with abnormal measurements (<10th centile).
Results
According to growth charts, there was an excess of FAS with abnormally small brain, isthmus, splenium, and vermis. According to scaling charts, this excess remained only for isthmus thickness and vermis height. The vermis foliation was pathological in 18% of those with FASD but in no comparison individual. Overall, 39% of those with FAS, 27% with NS‐FASD, but only 2% of comparison individuals presented with two FAS‐recurrent abnormalities, and 19% of those with FAS had all three. Considering the number of anomalies, there was a higher likelihood of a causal link with alcohol in 14% of those with NS‐FASD.
Interpretation
Our results suggest that adding an explicit composite neuroanatomical–radiological criterion for FASD diagnosis may improve its specificity, especially in NS‐FASD.
What this paper adds
Neuroanatomical anomalies independent of microcephaly can be measured with clinical‐imaging tools.
Small‐for‐age brain, small‐for‐brain‐size callosal isthmus or vermian height, and disrupted vermis foliation are fetal alcohol syndrome (FAS)‐recurrent anomalies.
Associations of these anomalies are frequent in fetal alcohol spectrum disorder (FASD) even without FAS, while exceptional in typically developing individuals.
These associations support higher likelihood of causal link with alcohol in some individuals with non‐syndromic FASD.
A new explicit and composite neuroanatomical–radiological criterion can improve the specificity of FASD diagnosis.
What this paper adds
Neuroanatomical anomalies independent of microcephaly can be measured with clinical‐imaging tools.
Small‐for‐age brain, small‐for‐brain‐size callosal isthmus or vermian height, and disrupted vermis foliation are fetal alcohol syndrome (FAS)‐recurrent anomalies.
Associations of these anomalies are frequent in fetal alcohol spectrum disorder (FASD) even without FAS, while exceptional in typically developing individuals.
These associations support higher likelihood of causal link with alcohol in some individuals with non‐syndromic FASD.
A new explicit and composite neuroanatomical–radiological criterion can improve the specificity of FASD diagnosis.
This study radiologically describes recurrent neuroanatomical anomalies in 89 individuals with fetal alcohol spectrum disorders (FASD): brain size deficiency, abnormalities of the corpus callosum and of the vermis. We originally showed that their combination is frequent not only in fetal alcohol syndrome (FAS) but also in non‐syndromic FASD while exceptional in 100 typically developing individuals. We proposed the addition of a neuroanatomical criterion in a new explicit and composite 'brain damage' score which increased the likelihood for a causal link with prenatal alcohol exposure for 14% of those with non‐syndromic FASD.
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.
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.
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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