Neuroprogenitor Cells From Patients With TBCK Encephalopathy Suggest Deregulation of Early Secretory Vesicle Transport

Biallelic pathogenic variants in TBCK cause encephaloneuropathy, infantile hypotonia with psychomotor retardation, and characteristic facies 3 (IHPRF3). The molecular mechanisms underlying its neuronal phenotype are largely unexplored. In this study, we reported two sisters, who harbored biallelic variants in TBCK and met diagnostic criteria for IHPRF3. We provided evidence that TBCK may play an important role in the early secretory pathway in neuroprogenitor cells (iNPC) differentiated from induced pluripotent stem cells (iPSC). Lack of functional TBCK protein in iNPC is associated with impaired endoplasmic reticulum-to-Golgi vesicle transport and autophagosome biogenesis, as well as altered cell cycle progression and severe impairment in the capacity of migration. Alteration in these processes, which are crucial for neurogenesis, neuronal migration, and cytoarchitecture organization, may represent an important causative mechanism of both neurodevelopmental and neurodegenerative phenotypes observed in IHPRF3. Whether reduced mechanistic target of rapamycin (mTOR) signaling is secondary to impaired TBCK function over other secretory transport regulators still needs further investigation.

Central Apneas Due to the CLIFAHDD Syndrome Successfully Treated with Pyridostigmine

NALCN mutations lead to complex neurodevelopmental syndromes, including infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) and congenital contractures of limbs and face, hypotonia, and developmental delay (CLIFAHDD), which are recessively and dominantly inherited, respectively. We present a patient in whom congenital myasthenic syndrome (CMS) was suspected due to the occurrence of hypotonia and apnea episodes requiring resuscitation. For this reason, treatment with pyridostigmine was introduced. After starting the treatment, a significant improvement was observed in reducing the apnea episodes and slight psychomotor progress. In the course of further diagnostics, CMS was excluded, and CLIFAHDD syndrome was confirmed. Thus, we try to explain a possible mechanism of clinical improvement after the introduction of treatment with pyridostigmine in a patient with a mutation in the NALCN gene.

Canavan Disease - A Rare Case Report

Canavan disease is a rare autosomal recessive disorder characterized by progressive leukodystrophy involving white matter of the brain. Disease leads to severe psychomotor retardation, seizures and premature death. More prevalent among Jewish population. Among non-Jewish population incidence is approximately 1:100000. Prognosis is guarded with current management only symptomatic and supportive. There is no effective treatment, however early gene therapy has improved the quality of life of patients. Furthermore, Lithium citrate has also shown certain positive results in experimental models using rats. Even few human studies have also been done, however promising results require larger controlled trials. Keywords: MRI: Magnetic Resonance and Imaging, EEG: Electro Encephalogram, CD: Canavan Disease, ASPA: acetyl aspartate, LUCS: Lower Uterine Cesarean Section, OFC: Occipito Frontal Circumference, NAA: N-acetyl aspartate

Cognitive and emotional aspects of patients with multiple sclerosis during illness and hospitalization process: Contributions of cognitive-behavioral therapy / Aspectos cognitivos e emocionais dos pacientes com esclerose múltipla durante a doença e o processo de hospitalização: Contribuições da terapia cognitivo-comportamental

Multiple Sclerosis (MS) is a demyelinating disease, characterized by lesions in the Central Nervous System (CNS) that affects its healthy cells, causing motor and neurological sequelae. This work aims to understand the psychological and emotional aspects of patients inserted into a hospital and diagnosed with MS. Thus, a narrative review of the literature was carried out, investigating the main topics related to the theme, and illustrated through the case report of three patients treated with brief cognitive-behavioral psychotherapy, in a tertiary healthcare center in 2021. The literature indicates that, commonly, 30 to 50% of individuals with the disease present significant cognitive impairment symptoms, such as dysarthria, executive dysfunction, and reduced processing speed, in addition to greater depressive symptoms and dysfunctional beliefs. The most common psychological phenomena in the cases referred to were maladaptive cognitive distortions, such as catastrophizing and negative filtering, as well as saddened affection and psychomotor retardation. Considering the common semiology presented by them, and also taking into consideration the characteristics of the family and the social and environmental context in which they are placed, it is evident that there is an influence of these factors on their belief systems and thoughts, as already predisposed characteristics or originated by the progression of the disease. Cognitive-Behavioral Therapy (CBT) techniques, such as motivational interviewing and psychoeducation, are shown to be effective for the treatment of dysfunctional comorbidities associated with the disease.

Compound Heterozygous ROBO3 Mutation in Two Siblings Presenting with Horizontal Gaze Palsy without Scoliosis: Case-Based Review

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare, autosomal recessively inherited disorder characterized by a congenital absence of conjugated horizontal eye movements with progressive scoliosis developing in childhood and adolescence. HGPPS is caused by mutations of the ROBO3 gene that disrupts the midline crossing of the descending corticospinal and ascending lemniscal sensory tracts in the medulla. We present two siblings, 5-year-old and 2-year-old boys with HGPPS, from non-consanguineous parents. The older brother was brought for the evaluation of moderate psychomotor retardation. He had bilateral horizontal gaze palsy with preserved vertical gaze and convergence. Scoliosis was absent. Cranial MRI showed brainstem abnormalities, and diffusion tensor imaging showed absent decussation of cortico-spinal tracts in the medulla. Clinical diagnosis of HGPPS was confirmed by sequencing of ROBO3 gene, IVS4–1G > A (c.767–1G > A) and c.328_329delinsCCC (p.Asp110Profs*57) compound heterozygous variations were found, and segregated in parents. The younger boy was first reported at 16 months of age and had the same clinical and neuroradiological findings, unlike mild psychomotor retardation. ROBO3 gene analysis showed the same variants in his brother. Our cases show the importance of evaluating eye movements in children with neurodevelopmental abnormalities and looking for brainstem abnormalities in children with bilateral horizontal gaze palsy.

Ketogenic diet as elective treatment in patients with drug-unresponsive hyperinsulinemic hypoglycemia caused by glucokinase mutations

Background Hyperinsulinemic hypoglycemia (HI) is the most frequent cause of recurrent hypoglycemia in children. Despite diagnostic and therapeutic advances, it remains an important cause of morbidity, leading to neurological complications, such as psychomotor retardation and epilepsy. Patients with diffuse drug-unresponsive HI manifest neurological impairment and neurobehavioral problems, even though surgically treated with a near-total pancreatectomy. Based on the analogies between HI and GLUT1 deficiency, both presenting with neuroglycopenia and lack of alternative cerebral energy sources, we administered a ketogenic diet (KD) in three drug-unresponsive GCK-HI patients with the aim of preserving neurodevelopment and avoiding the need of a near-total pancreatectomy. They presented recurrent symptomatic hypoglycemia, intellectual disability and refractory epilepsy. Patients were treated with classical KD for 79, 27 and 18 months, respectively. Results All patients became asymptomatic in a few days and showed an important improvement of the alert state. Epilepsy disappeared and no appearance of novel hypoglycemic lesions was detected with a brain MRI. Cognitive and adaptive abilities rapidly improved and normalized. IQ rose significantly from 81 to 111 (p = 0.04) in patient 1, from 82 vs 95 (p = 0.04) in patient 2, from 60 to 90 (p = 0.04) in patient 3. Conclusions We demonstrated the safety and efficacy of KD in the treatment of drug-unresponsive GCK-HI at a short and long-term. The neuroprotective effects of KD determined the recovery from epilepsy and intellectual disabilities and averted the need of a near-total pancreatectomy. All patients and their families reported an improvement of physical and psychosocial well-being, with a substantial improvement of their quality of life. These results might change the course and the quality of life of these patients and their families, having a relevant impact on human lives. Therefore, KD might be considered the elective treatment in unresponsive forms of GCK-HI.

Reward-Based Reinforcement Learning in Altered Among Individuals with a History of Major Depressive Disorder and Psychomotor Retardation Symptoms

Background: Reward-based reinforcement learning impairments are common in major depressive disorder, but it is unclear which reward-based reinforcement learning is disrupted in remitted major depression (rMDD). As the neurobiological substrates that implement reward-based RL are also strongly implicated in psychomotor retardation (PmR), the present study sought to test whether reward-based reinforcement learning is particularly altered in rMDD individuals with past PmR. Methods: Three groups of individuals (1) rMDD with past PmR (PmR+, N=34), rMDD without past PmR (PmR-, N=44) and healthy controls (N=90) completed a reward-based reinforcement learning task. Computational modeling was applied to test for group differences in model-derived parameters – specifically, learning rate, reward sensitivity, and value estimates. Results: Compared to controls, rMDD PmR + exhibited lower learning rates, but not reduced reward sensitivity. Relative to rMDD PmR-, rMDD PmR + exhibited reduced value estimation early, but not later, in the reinforcement learning task. Follow-up analyses indicated that the results were not due to current psychopathology symptoms.Conclusions: Results indicate that a history of PmR predicts altered reward-based reinforcement learning in rMDD. Abnormal reward-related reinforcement learning may reflect a scar of past depressive episodes that contained psychomotor symptoms, or a trait-like deficit that preceded these episodes.

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.

Case Report: Complete Maternal Uniparental Disomy of Chromosome 2 With a Novel UNC80 Splicing Variant c.5609-4G> A in a Chinese Patient With Infantile Hypotonia With Psychomotor Retardation and Characteristic Facies 2

Background: Infantile hypotonia with psychomotor retardation and characteristic facies 2 (IHPRF2) is a rare autosomal recessive neurodevelopmental disorder caused by mutations in the UNC80 gene. It is characterized by severe global developmental delay, poor or absent speech and absent or limited walking abilities. The current study explored a case of a Chinese patient with IHPRF2 caused by a novel splicing variant of UNC80.Case Report: The proband is a 8-year-old Chinese male manifested with global developmental delay, severe truncal hypotonia, absent speech and intellectual disability. SNP array analysis revealed a uniparental isodisomy of the entire chromosome 2 [UPD(2)] in the proband. Whole exome sequencing (WES) subsequently identified a novel mutation c.5609-4G&gt;A in the UNC80 gene, which was inherited from his mother and was confirmed by Sanger sequencing, indicating that UPD(2) was of maternal origin.Conclusion: A novel UNC80 homozygous splicing variant c.5609-4G&gt;A associated with maternal UPD(2) was identified. These findings indicate that UPD poses a high risk of autosomal recessive diseases, and provides information on the variant spectrum for UNC80. Our findings elucidate on understanding of the genotype-phenotype associations that occur in IHPRF2 patients.

The Role and Function of Regulatory T Cells in Toxoplasma gondii-Induced Adverse Pregnancy Outcomes

Infection with Toxoplasma gondii (T. gondii) during the pregnant period and its potentially miserable outcomes for the fetus, newborn, and even adult offspring continuously occur worldwide. People acquire infection through the consumption of infected and undercooked meat or contaminated food or water. T. gondii infection in pregnant women primarily during the gestation causes microcephaly, mental and psychomotor retardation, or death. Abnormal pregnancy outcomes are mainly associated with regulatory T cell (Treg) dysfunction. Tregs, a special subpopulation of T cells, function as a vital regulator in maintaining immune homeostasis. Tregs exert a critical effect on forming and maintaining maternal-fetal tolerance and promoting fetal development during the pregnancy period. Forkhead box P3 (Foxp3), a significant functional factor of Tregs, determines the status of Tregs. In this review, we summarize the effects of T. gondii infection on host Tregs and its critical transcriptional factor, Foxp3.