Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder.

BCAS3 microtubule-associated cell migration factor (BCAS3) is a large, highly conserved cytoskeletal protein previously proposed to be critical in angiogenesis and implicated in human embryogenesis and tumorigenesis. Here, we established BCAS3 loss-of-function variants as causative for a neurodevelopmental disorder. We report 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. The human phenotype is less severe compared with the Bcas3 knockout mouse model and cannot be explained by angiogenic defects alone. Consistent with being loss-of-function alleles, we observed absence of BCAS3 in probands' primary fibroblasts. By comparing the transcriptomic and proteomic data based on probands' fibroblasts with those of the knockout mouse model, we identified similar dysregulated pathways resulting from over-representation analysis, while the dysregulation of some proposed key interactors could not be confirmed. Together with the results from a tissue-specific Drosophila loss-of-function model, we demonstrate a vital role for BCAS3 in neural tissue development.

Current and future trends in multiple sclerosis management: Near East perspective.

BACKGROUND: Multiple sclerosis (MS) prevalence is rising in the Middle East. Most MS medications are available in the region, but not all, possibly affecting neurologists' prescribing habits. OBJECTIVES: To provide an overview of the current practices of Near East (NE) healthcare practitioners by probing their prescribing decisions, to report the COVID-19 impacts on neurologists' prescribing habits, and to explore the future relevance of current medication used in MS management among other newcomers. METHODS: A cross-sectional study was carried out using an online survey from April 27, 2022, to July 5, 2022. The questionnaire was designed with the input of five neurologists representing five NE countries (Iran, Iraq, Lebanon, Jordan & Palestine). They identified several factors that play a crucial role in the optimal care of MS patients. The link was shared among neurologists using snowball sampling. RESULTS: The survey included 98 neurologists. Effectiveness and safety balance was the most important factor considered when selecting the MS treatment. Among patients with MS, the most challenging factor for the patients was thought to be related to family planning, followed by affordability and tolerability of side effects. In the treatment of mild to moderate relapsing remitting multiple sclerosis (RRMS) in men, Interferon beta 1a SC, Fingolimod, and Glatiramer acetate were the most commonly recommended treatments. Dimethyl fumarate substituted fingolimod in female patients. Interferon beta 1a SC was the safest treatment for mild to moderate RRMS. Interferon beta 1a SC was preferred over other treatments for patients with mild to moderate MS and planning for pregnancy (56.6%) or breastfeeding (60.2%). Fingolimod was not a choice for these patients. Neurologists seemed to discuss the top three treatments of Natalizumab, Ocrelizumab, and Cladribine with patients with highly active MS. When asked to position future disease-modifying therapies five years from today, more than 45% of physicians expressed a lack of information on Bruton's tyrosine kinase (BTK) inhibitors. CONCLUSIONS: Most neurologists in the NE region followed Middle East North Africa Committee for Treatment and Research in Multiple Sclerosis (MENACTRIMS) recommendations for prescribing treatment. The treatment choice also depended on the availability of disease-modifying therapies (DMTs) in the region. Regarding the use of upcoming DMTs, there is a clear need for real-world data, long-term extension studies, and comparative studies to support their efficacy and safety profiles in treating patients with MS.

Right arm weakness and mouth deviation as a presentation of Primary Angiitis of the Central Nervous System treated with rituximab: A case-report.

Introduction: Primary Angiitis of the Central Nervous System (PACNS) is a rare form of vasculitis that solely affects the Central Nervous System (CNS). Its presentation varies widely from a simple headache to a stroke-like presentation. PACNS management is divided into an induction phase, which includes corticosteroids, cyclophosphamide and rituximab, and a maintenance phase which includes: methotrexate, mycophenolate mofetil, rituximab and azathioprine. Case presentation: A 31-year-old male presented to the emergency department due to an episode of right arm weakness and left-sided facial weakness. Brain Magnetic Resonance Imaging (MRI) would show an ischemic change in the frontal and parietal lobes. A biopsy was done, which showed inflammatory infiltrates consistent with Primary Angiitis of the Central Nervous System. The patient was started on rituximab and showed improvement. Clinical discussion: In this case, PACNS presented as episodic right arm weakness and left sided facial weakness. Gold standard for diagnosis is a biopsy from the inflamed region of the CNS that shows lymphocytic infiltration in a granulomatous pattern. Conclusion: Despite its rarity, PACNS is a cause of morbidity if not caught and managed early. Therefore, considering PACNS in the differential diagnosis of a young patient with a history of frequent episodic neurological dysfunction is appropriate. Ischemic patterns on MRI further increase the index of suspicion around PACNS Confirmation of the diagnosis via biopsy from the inflamed region is the most accurate method.

Late onset hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome, presenting as recurrent metabolic encephalopathy, A case report.

Introduction: and importance: Hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome (OMIM 238970) seems to be an autosomal recessive disorder caused by a mitochondrial ornithine transporter 1 deficiency, which results in urea cycle dysfunction. HHH is the most uncommon of the urea cycle diseases, with less than 100 cases recorded. Case presentation: A previously healthy 29 year old male presented to the emergency department complaining of decreased level of consciousness. CT scan, Cerebro-spinal-fluid analysis and toxicology screen were non-significant. Extended serum analysis showed elevated levels of ammonia. Urgent amino acid level analysis showed elevated ornithine. Follow up genetic testing showed that the patient is homozygous for the mutation c.44delG in exon 3 of SLC25A15 gene. Clinical discussion: In this case, HHH syndrome presented as a late-onset metabolic encephalopathy. For diagnosis; elevated levels of ammonia, ornithine accompanied by the abovementioned genetic mutation confirms the diagnosis. Treatment focuses on reduction of the ammonia levels using sodium benzoat, citrulline or arginine, and low protein diet. Conclusions: HHH syndrome, which is a urea cycle disorder, can present as a late-onset metabolic encephalopathy. High suspicion for genetic causes of metabolic encephalopathy should be maintained even for older patients without prior diagnosis in childhood/adolescence.

Impaired efficacy of spinal presynaptic mechanisms in spastic stroke patients.

Pathophysiological mechanisms underlying spasticity have been the subject of many studies. These studies performed in various kinds of spastic patients have revealed abnormalities in many spinal pathways controlling motoneurone discharge. Unfortunately, the pathophysiological mechanisms responsible for the development of spasticity remains nevertheless largely unknown since most of the previous studies failed to reveal a link between the characteristics of spasticity (severity, time course) and that of the dysfunction of a given perturbed spinal pathway. In the present series of experiments, we focused on the study of presynaptic mechanisms acting at the synapse fibre Ia-motoneurone since monosynaptic reflexes are enhanced in spasticity. Two presynaptic mechanisms have been described in both animals and humans: presynaptic Ia inhibition and post-activation depression. By increasing the number of subjects in comparison with previous studies (87 patients and 42 healthy controls) we have been able to show that these two mechanisms are unequally impaired in stroke patients depending on (i) the duration of the disease (acute, defined as less than 3 months after the causal lesion, or chronic, defined as more than 9 months after the causal lesion), (ii) the side considered (affected or unaffected) and (iii) the severity of spasticity. In this respect, only post-activation depression amount was found to be highly correlated with the severity of spasticity. Although not a definitive proof, this correlation between severity of spasticity and changes in a given spinal pathway lead us to conclude that the impairment of post-activation depression is likely one of the mechanisms underlying spasticity. On the contrary, changes in presynaptic Ia inhibition appear to be a simple epiphenomenon, i.e. a basic correlate of the brain lesions. It is argued that plastic changes develop from the disuse due to motor command impairment in both pathways.

Depression Reduces Accuracy While Parkinsonism Slows Response Time for Processing Positive Feedback in Patients with Parkinson's Disease with Comorbid Major Depressive Disorder Tested on a Probabilistic Category-Learning Task.

Major depressive disorder (MDD) is the most common non-motor manifestation of Parkinson's disease (PD) affecting 50% of patients. However, little is known about the cognitive correlates of MDD in PD. Using a computer-based cognitive task that dissociates learning from positive and negative feedback, we tested four groups of subjects: (1) patients with PD with comorbid MDD, (2) patients with PD without comorbid MDD, (3) matched patients with MDD alone (without PD), and (4) matched healthy control subjects. Furthermore, we used a mathematical model of decision-making to fit both choice and response time data, allowing us to detect and characterize differences between the groups that are not revealed by cognitive results. The groups did not differ in learning accuracy from negative feedback, but the MDD groups (PD patients with MDD and patients with MDD alone) exhibited a selective impairment in learning accuracy from positive feedback when compared to the non-MDD groups (PD patients without MDD and healthy subjects). However, response time in positive feedback trials in the PD groups (both with and without MDD) was significantly slower than the non-PD groups (MDD and healthy groups). While faster response time usually correlates with poor learning accuracy, it was paradoxical in PD groups, with PD patients with MDD having impaired learning accuracy and PD patients without MDD having intact learning accuracy. Mathematical modeling showed that both MDD groups (PD with MDD and MDD alone) were significantly slower than non-MDD groups in the rate of accumulation of information for stimuli trained by positive feedback, which can lead to lower response accuracy. Conversely, modeling revealed that both PD groups (PD with MDD and PD alone) required more evidence than other groups to make responses, thus leading to slower response times. These results suggest that PD patients with MDD exhibit cognitive profiles with mixed traits characteristic of both MDD and PD, furthering our understanding of both PD and MDD and their often-complex comorbidity. To the best of our knowledge, this is the first study to examine feedback-based learning in PD with MDD while controlling for the effects of PD and MDD.