STXBP1 Syndrome Is Characterized by Inhibition-Dominated Dynamics of Resting-State EEG

STXBP1 syndrome is a rare neurodevelopmental disorder caused by heterozygous variants in the STXBP1 gene and is characterized by psychomotor delay, early-onset developmental delay, and epileptic encephalopathy. Pathogenic STXBP1 variants are thought to alter excitation-inhibition (E/I) balance at the synaptic level, which could impact neuronal network dynamics; however, this has not been investigated yet. Here, we present the first EEG study of patients with STXBP1 syndrome to quantify the impact of the synaptic E/I dysregulation on ongoing brain activity. We used high-frequency-resolution analyses of classical and recently developed methods known to be sensitive to E/I balance. EEG was recorded during eyes-open rest in children with STXBP1 syndrome (n = 14) and age-matched typically developing children (n = 50). Brain-wide abnormalities were observed in each of the four resting-state measures assessed here: (i) slowing of activity and increased low-frequency power in the range 1.75–4.63 Hz, (ii) increased long-range temporal correlations in the 11–18 Hz range, (iii) a decrease of our recently introduced measure of functional E/I ratio in a similar frequency range (12–24 Hz), and (iv) a larger exponent of the 1/f-like aperiodic component of the power spectrum. Overall, these findings indicate that large-scale brain activity in STXBP1 syndrome exhibits inhibition-dominated dynamics, which may be compensatory to counteract local circuitry imbalances expected to shift E/I balance toward excitation, as observed in preclinical models. We argue that quantitative EEG investigations in STXBP1 and other neurodevelopmental disorders are a crucial step to understand large-scale functional consequences of synaptic E/I perturbations.

Spontaneous seizure and memory loss in mice expressing an epileptic encephalopathy variant in the calmodulin-binding domain of Kv7.2

Epileptic encephalopathy (EE) is characterized by seizures that respond poorly to antiseizure drugs, psychomotor delay, and cognitive and behavioral impairments. One of the frequently mutated genes in EE is KCNQ2, which encodes the Kv7.2 subunit of voltage-gated Kv7 potassium channels. Kv7 channels composed of Kv7.2 and Kv7.3 are enriched at the axonal surface, where they potently suppress neuronal excitability. Previously, we reported that the de novo dominant EE mutation M546V in human Kv7.2 blocks calmodulin binding to Kv7.2 and axonal surface expression of Kv7 channels via their intracellular retention. However, whether these pathogenic mechanisms underlie epileptic seizures and behavioral comorbidities remains unknown. Here, we report conditional transgenic cKcnq2+/M547V mice, in which expression of mouse Kv7.2-M547V (equivalent to human Kv7.2-M546V) is induced in forebrain excitatory pyramidal neurons and astrocytes. These mice display early mortality, spontaneous seizures, enhanced seizure susceptibility, memory impairment, and repetitive behaviors. Furthermore, hippocampal pathology shows widespread neurodegeneration and reactive astrocytes. This study demonstrates that the impairment in axonal surface expression of Kv7 channels is associated with epileptic seizures, cognitive and behavioral deficits, and neuronal loss in KCNQ2-related EE.

PMM2-CDG and nephrotic syndrome: a case report.

CDG are a group of diseases altering the glycosylation process. Enzymes involved have ubiquitous distribution with systemic involvement and high phenotypic variability. We report the case of a girl with central hypotonia, epilepsy and severe psychomotor delay diagnosed with phosphomannomutase 2 deficiency (PMM2-CDG) after presenting with nephrotic syndrome.

SYNGAP1 and Methylenetetrahydrofolate in Cerebrospinal Fluid: Cognitive Development after Oral Folate (5-Methyltetrahydrofolate) Supplementation in a 5-Year-Old Girl

Synaptic Ras GTPase-activating protein 1 (SYNGAP1), also called Ras-GAP 1 or RASA5, is a cerebral protein with a role in brain synaptic function. Its expression affects the development, structure, function, and plasticity of neurons. Mutations in the gene cause a neurodevelopment disorder termed mental retardation-type 5, also called SYNGAP1 syndrome. This syndrome can cause many neurological symptoms including pharmaco-resistant epilepsy, intellectual disability, language delay, and autism spectrum disorder. The syndrome naturally evolves as epileptic encephalopathy with handicap and low intellectual level. A treatment to control epilepsy, limit any decrease in social capacities, and improve intellectual development is really a challenging goal for these patients. The etiologic investigation performed in a 5-year-old girl with early epileptic absence seizures (onset at 6 months) and psychomotor delay (language) revealed a low methylenetetrahydrofolate level in cerebrospinal fluid in a lumbar puncture, confirmed by a second one (35 nmol/L and 50 nmol/L vs. 60–100 nmol/L normal), associated with normal blood and erythrocyte folate levels. Hyperhomocysteinemia, de vivo disease, and other metabolic syndromes were excluded by metabolic analysis. No genetic disorders (like methylenetetrahydrofolate reductase and methenyltetrahydrofolate synthetase) with folate metabolism were found. The physical examination showed only a minor kinetic ataxia. An oral folate (5-methyltetrahydrofolate) supplementation was started with oral vitamin therapy. The child showed good progress in language with this new treatment; epilepsy was well balanced with only one antiepileptic drug. The SYNGAP1 mutation was identified in this patient's genetic analysis. Since the start of folate supplementation/vitamin therapy, the patient's neurologic development has improved. To our knowledge, no association between these two pathologies has been linked and no patient with this SYNGAP1 mutation has ever showed much intellectual progress. Low cerebral methylenetetrahydrofolate levels could be associated with SYNGAP1 mutations. One of the hypotheses is the link of folate metabolism with epigenetic changes including methylation process. One inborn metabolic activity in folate metabolism may be associated with SYNGAP1 disease with epigenetic repercussions. Further studies should assess the link of SYNGAP1 and methyltetrahydrofolate and the evolution of SYNGAP1 patients with oral folate supplementation or vitamin therapy.

Pediatrics of disability: a comprehensive approach to the child with syndromic psychomotor delay

: Intellectual disability is the impairment of cognitive, linguistic, motor and social skills that contribute to the global level of intelligence that occurs in the pediatric age, and now comprises also the term “mental retardation” used in the past to describe the same impairments under 5 years of age. Intellectual disability involves 3% of the general population, also due to a genetic cause including chromosome aberrations to account for the 3–28% of intellectual disability. Between people with intellectual disabilities, the cause of the disorders was identified as a single gene disorder up to 12%, as multifactorial disorders up to 4%, and as genetic disorders up to 8.5%. Children affected by a malformation syndrome associated with mental retardation or intellectual disability represent a care challenge for the pediatrician. The presence of a multidisciplinary team is essential to manage the patient, trying to control the complications of the syndrome for promoting the correct psychophysical development. This encourages continuous follow-up of these children since the pediatrician is essential both in the clinical management of the syndrome and in facilitating the social integration of these children.

Co-Occurrence of Fragile X Syndrome with a Second Genetic Condition: Three Independent Cases of Double Diagnosis

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism caused by the instability of a CGG trinucleotide repeat in exon 1 of the FMR1 gene. The co-occurrence of FXS with other genetic disorders has only been occasionally reported. Here, we describe three independent cases of FXS co-segregation with three different genetic conditions, consisting of Duchenne muscular dystrophy (DMD), PPP2R5D--related neurodevelopmental disorder, and 2p25.3 deletion. The co-occurrence of DMD and FXS has been reported only once in a young boy, while in an independent family two affected boys were described, the elder diagnosed with FXS and the younger with DMD. This represents the second case in which both conditions coexist in a 5-year-old boy, inherited from his heterozygous mother. The next double diagnosis had never been reported before: through exome sequencing, a girl with FXS who was of 7 years of age with macrocephaly and severe psychomotor delay was found to carry a de novo variant in the PPP2R5D gene. Finally, a maternally inherited 2p25.3 deletion associated with a decreased level of the MYT1L transcript, only in the patient, was observed in a 33-year-old FXS male with severe seizures compared to his mother and two sex- and age-matched controls. All of these patients represent very rare instances of genetic conditions with clinical features that can be modified by FXS and vice versa.

A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family

Background L-2-hydroxyglutaric aciduria (L2HGA) is a rare neurometabolic disorder that occurs due to accumulation of L-2-hydroxyglutaric acid in the cerebrospinal fluid (CSF), plasma and urine. The clinical manifestation of L2HGA includes intellectual disability, cerebellar ataxia, epilepsy, speech problems and macrocephaly. Methods In the present study, we ascertained a multigenerational consanguineous Pakistani family with 5 affected individuals. Clinical studies were performed through biochemical tests and brain CT scan. Locus mapping was carried out through genome-wide SNP genotyping, whole exome sequencing and Sanger sequencing. For in silico studies protein structural modeling and docking was done using I-TASSER, Cluspro and AutoDock VINA tools. Results Affected individuals presented with cognitive impairment, gait disturbance, speech difficulties and psychomotor delay. Radiologic analysis of a male patient revealed leukoaraiosis with hypoattenuation of cerebral white matter, suggestive of hypomyelination. Homozygosity mapping in this family revealed a linkage region on chromosome 14 between markers rs2039791 and rs781354. Subsequent whole exome analysis identified a novel frameshift mutation NM_024884.3:c.180delG, p.(Ala62Profs*24) in the second exon of L2HGDH. Sanger sequencing confirmed segregation of this mutation with the disease phenotype. The identification of the most N-terminal loss of function mutation published thus far further expands the mutational spectrum of L2HGDH.

Genomic imbalance in a patient with two balanced translocations and abnormal phenotype

Представлены клинические и молекулярно-генетические результаты обследования пациента с задержкой психомоторного развития, аномалиями фенотипа и множественными врожденными пороками систем и органов. При стандартном цитогенетическом исследовании определены две реципрокные транслокации между хромосомами 2 и 6 и хромосомами 7 и 11, подтвержденные FISH-методом. Хромосомный микроматричный анализ позволил выявить делецию 6q14.1 в точке разрыва на длинном плече хромосомы 6. Делеция включает несколько десятков генов, в том числе гены PHIP, FILIP1, MYO6, HTR1B, IMPG1, EVOLV4, TENT5A, которые вероятнее всего ассоциированы с клиническими проявлениями у пациента. The results of clinical and molecular genetic study of the patient with psychomotor delay, phenotype abnormalities and multiple congenital malformations of systems and organs are presented. A standard cytogenetic study determined a double translocation between chromosomes 2 and 6 and chromosomes 7 and 11, confirmed by the FISH method. Chromosomal microarray analysis revealed a deletion of 6q14.1 region at the break point on the long arm of chromosome 6. The deletion involves several dozen genes, including PHIP, FILIP1, MYO6, HTR1B, IMPG1, EVOLV4, TENT5A genes, which are most likely associated with clinical symptoms in the patient.

Clinical Predictive Factors of Pathological EEG in Children with Febrile Seizures and Their Association with Subsequent Epileptic Seizures

The objective of this study was to identify clinical parameters predicting either a pathological EEG or a subsequent epileptic seizure (SES), based on the relation between paroxysmal EEG abnormalities and clinical features in children who presented at least one febrile seizure (FS). We collected data of children who presented to our department during the period 2013 to 2018 for EEG recording as part of their febrile seizure assessment. Only children aged between 1 month to 5 years were included. Both the clinical and EEG data were retrospectively collected and statistically studied. We performed a detailed analysis of the EEG recordings. SES was identified for patients with sufficient follow-up. A total of 120 children were included in the study, of whom 48% had EEG abnormalities. Psychomotor retardation (p = 0.002), completion of an EEG within 7 days of the last FS (p = 0.046), and late age (> 3 years) of the first FS onset (p = 0.021) were significantly associated with a pathological EEG. In multivariate analysis, performing early EEG (< 7 days from the last FS) (odds ratio [OR]: 2.35; p = 0.043; confidence interval [CI]: 1.028–5.375) and psychomotor retardation (OR: 4.19; p = 0.008; CI: 1.46–12) were independent predictors of a pathological EEG. Of 120 patients, 45 had a follow-up. However, only 10 (22.22%) had SES. Children with SES tended more to have a psychomotor delay, compared with children without SES (50% vs. 14.28%, p = 0.029). Moreover, the percentage of initial abnormal EEG in patients with SES was significantly higher than those without SES (70% vs. 34.28%, p = 0.05). Even though some FS characteristics predict EEG abnormalities, they are not always associated with SES. We highlight the importance of performing an EEG in the group of children who had both FS and psychomotor retardation. This is most likely the group at the highest risk of developing epilepsy.

13q Deletion Syndrome Involving RB1: Characterization of a New Minimal Critical Region for Psychomotor Delay

Retinoblastoma (RB) is an ocular tumor of the pediatric age caused by biallelic inactivation of the RB1 gene (13q14). About 10% of cases are due to gross-sized molecular deletions. The deletions can involve the surrounding genes delineating a contiguous gene syndrome characterized by RB, developmental anomalies, and peculiar facial dysmorphisms. Overlapping deletions previously found by traditional and/or molecular cytogenetic analysis allowed to define some critical regions for intellectual disability (ID) and multiple congenital anomalies, with key candidate genes. In the present study, using array-CGH, we characterized seven new patients with interstitial 13q deletion involving RB1. Among these cases, three patients with medium or large 13q deletions did not present psychomotor delay. This allowed defining a minimal critical region for ID that excludes the previously suggested candidate genes (HTR2A, NUFIP1, PCDH8, and PCDH17). The region contains 36 genes including NBEA, which emerged as the candidate gene associated with developmental delay. In addition, MAB21L1, DCLK1, EXOSC8, and SPART haploinsufficiency might contribute to the observed impaired neurodevelopmental phenotype. In conclusion, this study adds important novelties to the 13q deletion syndrome, although further studies are needed to better characterize the contribution of different genes and to understand how the haploinsufficiency of this region can determine ID.