Description of a novel patient with the TRPM3 recurrent p.Val837Met variant.

De novo heterozygous missense mutations in TRPM3 have been shown to cause developmental and epileptic encephalopathies (DEE). It is a very rare condition, as only 9 patients have been described to date. We report here a novel patient carrying the recurrent p.Val837Met variant and presenting new clinical features, such as trigonocephaly, expanding the phenotypical spectrum of the disease.

Reading Comprehension Impairment in Children With Neurofibromatosis Type 1 (NF1): The Need of Multimodal Assessment of Attention.

Attention span, which has been shown to have an impact on reading quality in many other conditions, is one of the main cognitive disorders of neurofibromatosis type 1 (NF1). The aim of this work is to observe the impact of attention on reading comprehension, in NF1 and non-NF1 children. A multicenter, cross-sectional study was conducted on 150 children (8-12 years old) with or without NF1 (75 NF1 vs 75 non-NF1; 72 female, 78 male), matched for age, sex, handedness, and reading level, thus forming a continuum from good to poor readers in both NF1 and non-NF1 groups. Children with intellectual deficiency or neurologic or psychiatric disorder were excluded. Attentional skills were assessed by combining a parent questionnaire (Child Behavior CheckList) and a performance-based assessment (Conner's Continuous Performance Test-Second Edition). Reading comprehension was assessed through a standardized reading comprehension test (ORLEC Lobrot). The performance-based attention scores were associated with text and sentence comprehension ability (P = .0235 and P = .0164, respectively), while indirect questionnaire attention scores were only associated with sentence comprehension (P = .0263). For both groups, the correlations between questionnaire and performance-based measures were low. We have shown that reading comprehension is greatly influenced by attention in NF1 and non-NF1, even if predictors of good reading comprehension also include IQ score and reading accuracy. Indirect observer-rated questionnaires and direct performance-based measures of attention do not assess the same variables, are linked to different components of reading skills, and are not interchangeable assessments of attention difficulties. Both assessments are complementary and must be used simultaneously, leading to recommendations that support multimodal assessment of attention.

New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics.

PURPOSE: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority. METHODS: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC. RESULTS: Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype-phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts. CONCLUSION: Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.

Defining the phenotype of FHF1 developmental and epileptic encephalopathy.

Fibroblast growth-factor homologous factor (FHF1) gene variants have recently been associated with developmental and epileptic encephalopathy (DEE). FHF1 encodes a cytosolic protein that modulates neuronal sodium channel gating. We aim to refine the electroclinical phenotypic spectrum of patients with pathogenic FHF1 variants. We retrospectively collected clinical, genetic, neurophysiologic, and neuroimaging data of 17 patients with FHF1-DEE. Sixteen patients had recurrent heterozygous FHF1 missense variants: 14 had the recurrent p.Arg114His variant and two had a novel likely pathogenic variant p.Gly112Ser. The p.Arg114His variant is associated with an earlier onset and more severe phenotype. One patient carried a chromosomal microduplication involving FHF1. Twelve patients carried a de novo variant, five (29.5%) inherited from parents with gonadic or somatic mosaicism. Seizure onset was between 1 day and 41 months; in 76.5% it was within 30 days. Tonic seizures were the most frequent seizure type. Twelve patients (70.6%) had drug-resistant epilepsy, 14 (82.3%) intellectual disability, and 11 (64.7%) behavioral disturbances. Brain magnetic resonance imaging (MRI) showed mild cerebral and/or cerebellar atrophy in nine patients (52.9%). Overall, our findings expand and refine the clinical, EEG, and imaging phenotype of patients with FHF1-DEE, which is characterized by early onset epilepsy with tonic seizures, associated with moderate to severe ID and psychiatric features.

Postnatal clinical phenotype of five patients with Pallister-Killian Syndrome (tetrasomy 12p): Interest of array CGH for diagnosis and review of the literature.

BACKGROUND: Pallister-Killian syndrome (PKS) is a rare sporadic disorder caused by tetrasomy of the short arm of chromosome 12. The main clinical manifestations are global developmental delay, intellectual disability, epilepsy, dysmorphic features, hypopigmented and/or hyperpigmented lesions, and multiple congenital anomalies. PKS is associated with tissue mosaicism, which is difficult to diagnose through peripheral blood sample by conventional cytogenetic methods and fluorescence in situ hybridization. METHODS: Here, we report five patients with PKS. We delineate their clinical phenotypes and we compare them with previously published cases. We used array Comparative Genomic Hybridization (aCGH) with DNA extracted from peripheral blood samples. The five patients have also been tested by conventional cytogenetics techniques. RESULTS: Four out of five patients showed tetrasomy 12p by aCGH. Three of the four patients have typical i(12p) and one of the four demonstrated atypical tetrasomy 12p. The percentage of mosaicism was as low as 20%. Our cohort exhibited the typical PKS phenotypes. CONCLUSION: Our results demonstrate the efficacy of aCGH for the diagnosis of PKS from DNA extracted from lymphocytes. Thus, for patients suspected of PKS, we recommend performing aCGH on lymphocytes at an early age before  proceeding to skin biopsy. aCGH on peripheral blood samples is sensitive in detecting low level of mosaicism and it is less invasive method than skin biopsy. We reviewed also the literature concerning the previously published PKS patients diagnosed by aCGH.

A novel truncating variant p.(Arg297*) in the GRM1 gene causing autosomal-recessive cerebellar ataxia with juvenile-onset.

GRM1 gene, that is located on 6q24.3, encodes the metabotropic glutamate receptor type 1 (mGluR1), a transmembrane protein highly expressed in cerebellar Purkinje cells. Pathogenic variants in GRM1 have been reported only three times in humans, causing autosomal-recessive cerebellar ataxia with early-onset and intellectual disability or dominant forms of cerebellar ataxia with less severe phenotype in adults. We report a six-year-old boy, born to inbred parents, with an early-onset cerebellar syndrome due to a homozygous autosomal-recessive GRM1 pathogenic variant. In addition to cerebellar ataxia, axial hypotonia and oculomotor signs, he showed a severe and global developmental delay with lack of walking and speech and slight facial dysmorphic features. Brain MRI, performed at 1 year and at 5 years, showed a slowly progressive cerebellar atrophy. A novel homozygous truncating variant in the second exon of GRM1 gene (c.889C>T, p.(Arg297*)), inherited from the heterozygous healthy parents, was found by exome sequencing. Our observation not only emphasizes the central role of mGluR1-mediated signaling in cerebellar function and neurodevelopment but also provides valuable insights into the early clinical signs of recessive ataxia due to GRM1 pathogenic variants that were not reported previously. The difficulties of clinical differential diagnosis between this disease and other forms of congenital ataxia and the unspecific cerebellar atrophy on MRI highlight the importance of large-scale genetic investigations.

Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures.

CYFIP2, encoding the evolutionary highly conserved cytoplasmic FMRP interacting protein 2, has previously been proposed as a candidate gene for intellectual disability and autism because of its important role linking FMRP-dependent transcription regulation and actin polymerization via the WAVE regulatory complex (WRC). Recently, de novo variants affecting the amino acid p.Arg87 of CYFIP2 were reported in four individuals with epileptic encephalopathy. We here report 12 independent patients harboring a variety of de novo variants in CYFIP2 broadening the molecular and clinical spectrum of a novel CYFIP2-related neurodevelopmental disorder. Using trio whole-exome or -genome sequencing, we identified 12 independent patients carrying a total of eight distinct de novo variants in CYFIP2 with a shared phenotype of intellectual disability, seizures, and muscular hypotonia. We detected seven different missense variants, of which two occurred recurrently (p.(Arg87Cys) and p.(Ile664Met)), and a splice donor variant in the last intron for which we showed exon skipping in the transcript. The latter is expected to escape nonsense-mediated mRNA decay resulting in a truncated protein. Despite the large spacing in the primary structure, the variants spatially cluster in the tertiary structure and are all predicted to weaken the interaction with WAVE1 or NCKAP1 of the actin polymerization regulating WRC-complex. Preliminary genotype-phenotype correlation indicates a profound phenotype in p.Arg87 substitutions and a more variable phenotype in other alterations. This study evidenced a variety of de novo variants in CYFIP2 as a novel cause of mostly severe intellectual disability with seizures and muscular hypotonia.

MOG antibody-related disorders: common features and uncommon presentations.

Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) have been reported in acute demyelinating encephalomyelitis (ADEM), optic neuritis (ON), and neuromyelitis optica spectrum disorders (NMOSD) in adults and pediatrics. We aimed to delineate the common features of MOG-Ab-related disorders in children and adults, and report uncommon presentations. Twenty-seven consecutive pediatric and adult patients testing positive for MOG-Ab, with a minimum follow-up of 6 months, were included. Comprehensive epidemiological, clinical, radiological, and laboratory data were retrospectively analyzed. Additionally, we compared radiological features between ADEM MOG-Ab-positive patients, and a group of ADEM MOG-Ab-negative ones, recruited during the same period. Among the whole cohort, 13 (48.1%) were pediatric, and 14 (51.9%) were female. MOG-Ab-related disorders comprised eight ADEM, eight ON, five isolated myelitis, four with NMOSD and two patients with multiple sclerosis, at last follow-up. After a median follow-up of 17.8 months, 11 (40.7%) patients presented a relapse. The most frequent clinical phenotype at onset was encephalopathy in pediatrics (53.9%) and myelitis in adults (50%) (p = 0.013). There were no other differences between both groups. When comparing ADEM MOG-Ab positive and negative patients, bilateral thalamic lesions were more often found in the positive group (p = 0.010). Unusual presentations were identified in three patients: patchy spinal cord gadolinium-enhancing lesions, an associated teratoma, and one presented with status epilepticus. MOG-Ab-related disorders shared common clinical and prognostic features, but encompass a spectrum wider than recently reported.

Novel homozygous missense variant of GRIN1 in two sibs with intellectual disability and autistic features without epilepsy.

We report on two consanguineous sibs affected with severe intellectual disability and autistic features due to a homozygous missense variant of GRIN1. Massive parallel sequencing was performed using a gene panel including 450 genes related to intellectual disability and autism spectrum disorders. We found a homozygous missense variation of GRIN1 (c.679G>C; p.(Asp227His)) in the two affected sibs, which was inherited from both unaffected heterozygous parents. Heterozygous variants of GRIN1, encoding the GluN1 subunit of the NMDA receptor, have been reported in patients with neurodevelopmental disorders including epileptic encephalopathy, severe intellectual disability, and movement disorders. The p.(Asp227His) variant is located in the same aminoterminal protein domain as the recently published p.(Arg217Trp), which was found at the homozygous state in two patients with a similar phenotype of severe intellectual disability and autistic features but without epilepsy. In silico predictions were consistent with a deleterious effect. The present findings further expand the clinical spectrum of GRIN1 variants and support the existence of hypomorphic variants causing severe neurodevelopmental impairment with autosomal recessive inheritance.

Systematic MRI in NF1 children under six years of age for the diagnosis of optic pathway gliomas. Study and outcome of a French cohort.

BACKGROUND/PURPOSE: Optic pathway glioma (OPG) is the most common central nervous system tumor in children with neurofibromatosis type 1 (NF1), affecting 15-20% of patients. We reviewed the medical records of children systematically screened by ophthalmologic and MRI examinations to determine the influence of screening on the therapeutic management of children with OPG. METHODS: Data were collected on 306 newly diagnosed cases screened with systematic MRI from January 2001 to July 2007. In the OPG group, we distinguished the asymptomatic or symptomatic groups according to their initial status. RESULTS: Forty-five patients had confirmed OPG (14.7%). Thirty-six patients (80%) were asymptomatic and nine (20%) were symptomatic at the time of diagnosis with visual symptoms in six cases. The average age at OPG diagnosis was 3.4 years with six patients (13%) over six years old. Average follow-up was 7.7 years. Progression was observed in 16 cases (35%). Most patient conditions were managed conservatively (87%). Six children (13%) were treated with chemotherapy due to worsening visual function. All of these children had severe or mild visual impairment at the end of follow-up. CONCLUSION: Our study does not support a clear benefit of systematic MRI screening in NF1 children under six years old. Systematic neuroimaging in our study did not influence therapeutic management. Although OPG diagnosis was made early, treatment with chemotherapy did not improve the final visual outcome. If MRI remains the best tool for the diagnosis of cerebral and spinal pathologies in the NF1 population, our current study questions the usefulness of systematic MRI screening for OPG diagnosis. Conversely, this study suggests that the indication of neuroimaging should be dictated by the results of annual clinical and ophthalmological assessments.

Nevus anemicus in neurofibromatosis type 1: a potential new diagnostic criterion.

BACKGROUND: Children with multiple café-au-lait macules (CALMs) may be followed for years before a second National Institutes of Health clinical criterion of neurofibromatosis type 1 (NF1) develops to confirm the diagnosis. OBJECTIVE: We sought to assess the prevalence of nevus anemicus (NA) in NF1 and its association with neuro-ophthalmologic complications. METHODS: This was a prospective multicenter case-control study of 210 consecutive patients with multiple CALMs. Patients with NF1 were matched for age, sex, and center with control subjects. We documented the number, location, and morphologic appearance of NA; dermatologic features of NF1; magnetic resonance imaging results; and family history. RESULTS: In all, 77 (51%) patients with NF1 had NA compared with 6 (2%) control subjects. NA was not detected in 26 patients with other genodermatoses associated with CALMs. Patients with NF1 and NA were younger than those without NA (median age: 17 years) (P = .002). NA was mostly localized to the upper anterior aspect of the chest. NA was not significantly linked with other clinical manifestations of NF1, including optic glioma and unidentified bright objects. LIMITATIONS: A potential referral bias associated with tertiary care centers is a limitation. CONCLUSIONS: NA appears to have a high prevalence and specificity in NF1 and might serve as a marker for NF1 in children with multiple CALMs.

Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2.

BACKGROUND: Early onset epileptic encephalopathies (EOEEs) are dramatic heterogeneous conditions in which aetiology, seizures and/or interictal EEG have a negative impact on neurological development. Several genes have been associated with EOEE and a molecular diagnosis workup is challenging since similar phenotypes are associated with mutations in different genes and since mutations in one given gene can be associated with very different phenotypes. Recently, de novo mutations in KCNQ2, have been found in about 10% of EOEE patients. Our objective was to confirm that KCNQ2 was an important gene to include in the diagnosis workup of EOEEs and to fully describe the clinical and EEG features of mutated patients. METHODS: We have screened KCNQ2 in a cohort of 71 patients with an EOEE, without any brain structural abnormality. To be included in the cohort, patient's epilepsy should begin before three months of age and be associated with abnormal interictal EEG and neurological impairment. Brain MRI should not show any structural abnormality that could account for the epilepsy. RESULTS: Out of those 71 patients, 16 had a de novo mutation in KCNQ2 (23%). Interestingly, in the majority of the cases, the initial epileptic features of these patients were comparable to those previously described in the case of benign familial neonatal epilepsy (BFNE) also caused by KCNQ2 mutations. However, in contrast to BFNE, the interictal background EEG was altered and displayed multifocal spikes or a suppression-burst pattern. The ongoing epilepsy and development were highly variable but overall severe: 15/16 had obvious cognitive impairment, half of the patients became seizure-free, 5/16 could walk before the age of 3 and only 2/16 patient acquired the ability to speak. CONCLUSION: This study confirms that KCNQ2 is frequently mutated de novo in neonatal onset epileptic encephalopathy. We show here that despite a relatively stereotyped beginning of the condition, the neurological and epileptic evolution is variable.