Eosinophilic Pleocytosis in the Cerebrospinal Fluid following CAR-T Cell Therapy for Central Nervous System Lymphoma: A Case for Warning?

INTRODUCTION: Chimeric antigen receptor T (CAR-T) cell therapy, emerging as an efficient treatment option for patients with secondary central nervous system (CNS) lymphoma, is frequently complicated with immune effector cell-associated neurotoxicity syndrome (ICANS). CASE PRESENTATION: We report a case of a 64-year-old woman with transformed follicular lymphoma, developing high-grade ICANS with eosinophilic pleocytosis following third-line therapy with CAR-T cells (tisagenlecleucel). During bridging therapy, she declined neurologically and was diagnosed with secondary CNS lymphoma. She received methotrexate-cytarabine-thiotepa-rituximab regimen with clinical and radiological improvement. Post-CAR-T cell infusion she developed cytokine release syndrome grade II and ICANS grade III. Given the lack of response to steroids, anakinra was initiated with complete ICANS resolution. Cerebrospinal fluid (CSF) analysis, performed only on day +10 due to thrombocytopenia, revealed eosinophils, while infections were excluded. CONCLUSION: This report emphasizes the importance of CSF analysis in individuals with CAR-T-related neurotoxicity for elucidating the role of specific immune cells in such complications.

Unveiling the vulnerability of the human abducens nerve: insights from comparative cranial base anatomy in mammals and primates.

The topographic anatomy of the abducens nerve has been the subject of research for more than 150 years. Although its vulnerability was initially attributed to its length, this hypothesis has largely lost prominence. Instead, attention has shifted toward its intricate anatomical relations along the cranial base. Contrary to the extensive anatomical and neurosurgical literature on abducens nerve anatomy in humans, its complex anatomy in other species has received less emphasis. The main question addressed here is why the human abducens nerve is predisposed to injury. Specifically, we aim to perform a comparative analysis of the basicranial pathway of the abducens nerve in mammals and primates. Our hypothesis links its vulnerability to cranial base flexion, particularly around the sphenooccipital synchondrosis. We examined the abducens nerve pathway in various mammals, including primates, humans (N = 40; 60% males; 40% females), and human fetuses (N = 5; 60% males; 40% females). The findings are presented at both the macroscopic and histological levels. To associate our findings with basicranial flexion, we measured the cranial base angles in the species included in this study and compared them to data in the available literature. Our findings show that the primitive state of the abducens nerve pathway follows a nearly flat (unflexed) cranial base from the pontomedullary sulcus to the superior orbital fissure. Only the gulfar segment, where the nerve passes through Dorello's canal, demonstrates some degree of variation. We present evidence indicating that the derived state of the abducens pathway, which is most pronounced in humans from an early stage of development, is characterized by following the significantly more flexed basicranium. Overall, the present study elucidates the evolutionary basis for the vulnerability of the abducens nerve, especially within its gulfar and cavernous segments, which are situated at the main synchondroses between the anterior, middle, and posterior cranial fossae-a unique anatomical relation exclusive to the abducens nerve. The principal differences between the pathways of this nerve and those of other cranial nerves are discussed. The findings suggest that the highly flexed human cranial base plays a pivotal role in the intricate anatomical relations and resulting vulnerability of the abducens nerve.

Mechanism underlying painful radiculopathy in patients with lumbar disc herniation.

BACKGROUND: Painful lumbar radiculopathy is a neuropathic pain condition, commonly attributed to nerve root inflammation/compression by disc herniation. The present exploratory study searched for associations between pain intensity and inflammatory markers, herniated disc size, infection, psychological factors and pain modulation in patients with confirmed painful lumbar radiculopathy scheduled for spine surgery. METHODS: Prior to surgery, 53 patients underwent the following evaluation: pain intensity measured on a 0-10 numeric rating scale (NRS) and the Short-Form McGill Pain Questionnaire; sensory testing (modified DFNS protocol); pain processing including temporal summation and conditioned pain modulation (CPM); neurological examination; psychological assessment including Spielberger's Anxiety Inventory, Pain Sensitivity Questionnaire and the Pain Catastrophizing Scale. Pro-inflammatory cytokine levels (IL-1b, IL-6, IL-8, IL-17, TNFα, IFNg) and microbial infection (ELISA and rt-PCR) in blood and disc samples obtained during surgery. MRI scans assessments for disc herniation size/volume (MSU classification/ three-dimensional volumetric analysis). RESULTS: Complete data were available from 40 (75%) patients (15 female) aged 44.8 ± 16.3 years. Pain intensity (NRS) positively correlated with pain catastrophizing and CPM (r = 0.437, p = 0.006; r = 0.421, p = 0.007; respectively), but not with disc/blood cytokine levels, bacterial infection or MRI measures. CPM (p = 0.001) and gender (p = 0.029) were associated with average pain intensity (adjusted R2  = 0.443). CONCLUSIONS: This exploratory study suggests that pain catastrophizing, CPM and gender, seem to contribute to pain intensity in patients with painful lumbar radiculopathy. The role of mechanical compression and inflammation in determining the intensity of painful radiculopathy remains obscure. SIGNIFICANCE OF STUDY: Pain catastrophizing, CPM and gender rather than objective measures of inflammation and imaging seem to contribute to pain in patients with painful radiculopathy.

Congenital Hypotonia: Cracking a SAGA of consanguineous kindred harboring four genetic variants.

BACKGROUND: We aimed to determine the molecular and biochemical basis of an extended highly consanguineous family with multiple children presenting severe congenital hypotonia. METHODS: Clinical investigations, homozygosity mapping, linkage analyses and whole exome sequencing, were performed. mRNA and protein levels were determined. Population screening was followed. RESULTS: We have identified a novel nonsense variant in NGLY1 in two affected siblings, and compound heterozygosity for three novel RYR1 variants in two affected sisters from another nuclear family within the broad pedigree. Population screening revealed a high prevalence of carriers for both diseases. The genetic variants were proven to be pathogenic, as demonstrated by western blot analyses. CONCLUSIONS: Revealing the genetic diagnosis enabled us to provide credible genetic counselling and pre-natal diagnosis to the extended family and genetic screening for this high-risk population. Whole exome/genome sequencing should be the first tier tool for accurate determination of the genetic basis of congenital hypotonia. Two different genetic disorders within a large consanguineous pedigree should be always considered.

Changes in Brain Volume Resulting from Cognitive Intervention by Means of the Feuerstein Instrumental Enrichment Program in Older Adults with Mild Cognitive Impairment (MCI): A Pilot Study.

There is increasing interest in identifying biological and imaging markers for the early detection of neurocognitive decline. In addition, non-pharmacological strategies, including physical exercise and cognitive interventions, may be beneficial for those developing cognitive impairment. The Feuerstein Instrumental Enrichment (FIE) Program is a cognitive intervention based on structural cognitive modifiability and the mediated learning experience (MLE) and aims to promote problem-solving strategies and metacognitive abilities. The FIE program uses a variety of instruments to enhance the cognitive capacity of the individual as a result of mediation. A specific version of the FIE program was developed for the cognitive enhancement of older adults, focusing on strengthening orientation skills, categorization skills, deductive reasoning, and memory. We performed a prospective interventional pilot observational study on older subjects with MCI who participated in 30 mediated FIE sessions (two sessions weekly for 15 weeks). Of the 23 subjects who completed the study, there was a significant improvement in memory on the NeuroTrax cognitive assessment battery. Complete sets of anatomical MRI data for voxel-based morphometry, taken at the beginning and the end of the study, were obtained from 16 participants (mean age 83.5 years). Voxel-based morphometry showed an interesting and unexpected increase in grey matter (GM) in the anterolateral occipital border and the middle cingulate cortex. These initial findings of our pilot study support the design of randomized trials to evaluate the effect of cognitive training using the FIE program on brain volumes and cognitive function.

Bariatric Surgery-Associated Myelopathy.

Bariatric surgery is gaining acceptance as an efficient treatment modality for adults and adolescents with morbid obesity. The early postbariatric period has the potential to induce an immunomodulatory imbalance due to the development or worsening of nutritional deficiencies, changes in hormonal balance (specifically after sleeve gastrectomy), and a shift in the proinflammatory cytokine profile along with a major change in the gut microbiome and permeability. These changes may induce encephalomyelitic T cell activity, change neural barrier permeability, and induce gut dysbioisis, favoring a proinflammatory metabolic profile. Such changes, in genetically prone individuals or those with additional risk factors, may lead to the development of myelopathy, particularly MS. Key Message: Postbariatric myelopathy is rare but should be considered in bariatric patients with relevant complaints in the postoperative period.

Leptomeningeal carcinomatosis or ischemic cerebrovascular disease?

A lung cancer patient suspected to have leptomeningeal carcinomatosis was referred for radiation. A careful evaluation of the MRI by a neuroradiologist revealed multiple brain infarcts. Multidisciplinary meetings are important for patient's case.

Diagnostic correlation between clinical protocols and magnetic resonance findings in temporomandibular disorders: A systematic review and meta-analysis.

BACKGROUND: Our aim was to assess the diagnostic correlation between clinical protocols and magnetic resonance (MRI) findings in temporomandibular disorders (TMDs), including disc displacement with and without reduction (DDwR; DDwoR) and arthralgia. METHODS: A systematic review performed in two phases according to the PRISMA checklist. Specific indexing terms were used for search of studies assessing TMDs through clinical diagnostic protocols with the aid of Research Diagnostic Criteria for TMDs or Diagnostic Criteria for TMDs. Quality assessment performed using QUADAS-2. Heterogeneity was assessed using I2 . Publication bias was assessed using funnel plots. For meta-analysis, we used random effect model or fixed effect. The main outcomes were sensitivity and specificity of clinical protocols. RESULTS: Fourteen studies included in the qualitative analysis and 11 studies in the meta-analysis. None of the studies fulfilled all criteria of QUADAS-2. High heterogeneity and high publication bias were found among the studies. Clinical protocols for assessing DDwR compared with MRI showed pooled sensitivity of 66% and specificity of 72%. For DDwoR, sensitivity was 61% and specificity 98%. For arthralgia, sensitivity was 43% and specificity 68% for the presence of effusion. CONCLUSIONS: This review reveals the need for studies with improved quality. Clinical protocols show poor to moderate validity in diagnosis of DDwR and DDwoR compared with MRI. No correlation was found between a clinical diagnosis of arthralgia and MRI effusion. Clinical diagnostic protocols can be used as screening tools, reserving the use of MRI for a more accurate diagnosis in patients with symptoms or dysfunction.

Long-Term Quality of Life after Endoscopic Pituitary Adenoma Surgery with Nasoseptal Flap Reconstruction.

INTRODUCTION: Endoscopic endonasal transsphenoidal surgery (EETS) on the pituitary gland is considered safe and efficacious. The nasoseptal flap (NSF) is sometimes used to prevent or repair postoperative cerebrospinal fluid (CSF) leaks. Few investigators have quantified long-term quality-of-life (QOL) outcomes regarding sinonasal measures after EETS, with or without involvement of the NSF. This study assesses whether the septal flap affects sinonasal QOL outcomes for patients receiving EETS for pituitary adenoma. METHODS AND MATERIALS: This is a retrospective study of patients who underwent EETS between 2013 and 2018. A total of 62 adults completed the Sinonasal Outcome Test-22 (SNOT-22) at least one year after the surgery. Outcome measures were compared between patients who underwent EETS with and without septal flap reconstruction. RESULTS: For the entire cohort, there were 14 patients (22.6%) who had septal flap reconstruction and 48 patients (77.4%) who did not. Patient demographics, tumor characteristics, surgical outcomes, and duration between surgery and completion of the questionnaire were similar for both groups. The mean SNOT-22 scores in the no reconstruction (NR) group and the nasoseptal flap reconstruction (NSFR) group were similar (P=0.9). In terms of SNOT-22 subdomains (rhinologic symptoms, extranasal rhinologic symptoms, ear/facial symptoms, psychological dysfunction, and sleep dysfunction), no significant differences were found when comparing the groups. CONCLUSION: As compared with no reconstructive involvement, NSF utilization does not affect the QOL and nasal symptoms of patients undergoing EETS.

Q Fever Vertebral Osteomyelitis Complicating Vertebroplasty.

Query (Q) fever is a zoonotic bacterial infection caused by Coxiella burnetii. In a minority of patients, chronic disease can occur after acute infection. Endocarditis and infections of aneurysms or vascular prostheses are the most common forms of chronic Q fever in adults. We report a case of an elderly female patient with chronic Q fever vertebral osteomyelitis at the site of her previous cement vertebroplasty, complicated by paravertebral abscess. Patient treatment required prolonged drainage in addition to the long duration of antibiotic treatment by doxycycline and hydroxychloroquine. Osteomyelitis is a rare clinical presentation in adults with chronic Q fever. However, it is important to consider Q fever in the differential diagnosis of culture-negative osteomyelitis, especially in countries where C. burnetii is endemic, such as Israel.

COG6-CDG: Expanding the phenotype with emphasis on glycosylation defects involved in the causation of male disorders of sex development.

COG6-congenital disorder of glycosylation (COG6-CDG) is caused by biallelic mutations in COG6. To-date, 12 variants causing COG6-CDG in less than 20 patients have been reported. Using whole exome sequencing we identified two siblings with a novel homozygous deletion of 26 bp in COG6, creating a splicing variant (c.518_540 + 3del) and a shift in the reading frame. The phenotype of COG6-CDG includes growth and developmental retardation, microcephaly, liver and gastrointestinal disease, hypohydrosis and recurrent infections. We report two patients with novel phenotypic features including bowel malrotation and ambiguous genitalia, directing attention to the role of glycoprotein metabolism in the causation of disorders of sex development (DSD). Searching the glycomic literature, we identified 14 CDGs including males with DSD, a feature not previously accentuated. This study broadens the genetic and phenotypic spectrum of COG6-CDG and calls for increasing awareness to the central role of glycosylation processes in development of human sex and genitalia.

Survival impact of the time gap between surgery and chemo-radiotherapy in Glioblastoma patients.

Glioblastoma treatment protocol includes chemo-radiation (CRT) after maximal safe resection. However, the recommended time-gap between surgery and CRT is unclear, most trials protocol required an interval of less than 6 weeks. In the current study we evaluated the association of the time-gap between surgery and CRT to overall survival (OS) and progression free survival (PFS) in a tertiary center. After ethics committee approval, a retrospective study was conducted. Data was collected from the medical records of consecutive glioblastoma patients treated between 2005-2014. Parameters of interest included: background characteristics of patients, treatment dates and type of treatment, treatment interruptions and survival. Only patients who were diagnosed with WHO IV, underwent surgical resection (any type), and treated with postoperative CRT were included. For the analysis, patients were divided into 3 groups according to the time gap from surgery to CRT: <4 weeks, 4-6 weeks and >6 weeks. Overall survival and PFS were investigated using the Kaplan-Meier method and Cox proportional hazard model. Out of 465 patients, 204 were included. Median age was 60 years (range: 23-79 years) and 61.7% male vs. 38.3% female. There was a significant difference in OS (HR = 0.49, p-value = 0.002, 95% CI: 0.32-0.78) and PFS (HR = 0.51, p-value = 0.003, 95% CI: 0.33-0.79) in the group who was treated with CRT 6 weeks or more after surgery, compared with the other two groups tested. In our study, 6 weeks or more time-gap (median of 8 weeks) between surgery and CRT was associated with better OS and PFS among newly diagnosed glioblastoma patients. Our results are probably subjected to unaccounted biases of a retrospective study, and that CRT in this patient population is an effective therapy that overcomes the potential harm of initiating therapy later than 6 weeks. Our current approach is to initiate CRT within 6 weeks after surgery, similar to what is recommended in the literature, but the data from this study provide us with information that no major harms was done in patients who were delayed.

Tremor Relief and Structural Integrity after MRI-guided Focused US Thalamotomy in Tremor Disorders.

Background MRI-guided focused US thalamotomy of ventral intermediate nucleus of the thalamus is a treatment for tremor disorders. Purpose To evaluate white matter integrity before and after thalamotomy and its correlation with clinical outcome. Materials and Methods Participants with essential tremor (ET) or Parkinson disease (PD) undergoing thalamotomy were prospectively recruited between March 2016 and October 2018. Tremor and quality of life were assessed before, 1 month after, and 6 months after thalamotomy. Participants underwent T1-weighted, T2-weighted fluid-attenuated image recovery, and diffusion-tensor MRI before and 1 day, 7-10 days, 1-3 months, and 6 months or longer after treatment. Diffusivity and fiber tractography measures were calculated. Repeated measures analysis of variance with post hoc paired t test and Skillings-Mack test with post hoc Wilcoxon signed-rank test were used for normally and nonnormally distributed data, respectively, and Bonferroni method corrected for multiple comparisons. Results Twenty-two study participants with ET (mean age, 72 years ± 6 [standard deviation]; 14 men), 17 participants with PD (mean age, 65 years ± 8; 13 men), and a replication set of 17 participants with ET (mean age, 73 years ± 6; 10 men) were evaluated. Long-term damage was found in the ablated core (mean fractional anisotropy [FA] at baseline, 0.41 ± 0.10, and at ≥6 months, 0.23 ± 0.09; P < .001) and thalamus to red nucleus tract (mean number of tracts at baseline, 1663, and at ≥6 months, 1070; P = .003). Negative correlation was observed between motor thalamus FA 1 day after ablation and tremor improvement (ET: R = -0.52 [P = .03]; PD: R = -0.61 [P = .003]). Better tremor relief in ET was associated with lower fractional anisotropy before treatment (R = -0.5; P = .02). Conclusion MRI-guided focused US thalamotomy resulted in short- and long-term white-matter changes. Diffusion-tensor imaging provided evidence for long-term damage in the ablation core and in the thalamus and red nucleus tract, and a correlation between preablation fractional anisotropy in the motor thalamus and clinical outcome. © RSNA, 2020 Online supplemental material is available for this article.

Tumor Board Report: The value of tissue diagnosis.

Intracranial lesions in the presence of a known cancer are highly suspicious for brain metastases. Lung cancer is the most common solid tumor responsible for brain metastases. This case emphasizes the importance of multidisciplinary tumor boards including a dedicated neuroradiologist in the management of patients with cancer.

Biallelic DMXL2 mutations impair autophagy and cause Ohtahara syndrome with progressive course.

Ohtahara syndrome, early infantile epileptic encephalopathy with a suppression burst EEG pattern, is an aetiologically heterogeneous condition starting in the first weeks or months of life with intractable seizures and profound developmental disability. Using whole exome sequencing, we identified biallelic DMXL2 mutations in three sibling pairs with Ohtahara syndrome, belonging to three unrelated families. Siblings in Family 1 were compound heterozygous for the c.5135C>T (p.Ala1712Val) missense substitution and the c.4478C>G (p.Ser1493*) nonsense substitution; in Family 2 were homozygous for the c.4478C>A (p.Ser1493*) nonsense substitution and in Family 3 were homozygous for the c.7518-1G>A (p.Trp2507Argfs*4) substitution. The severe developmental and epileptic encephalopathy manifested from the first day of life and was associated with deafness, mild peripheral polyneuropathy and dysmorphic features. Early brain MRI investigations in the first months of life revealed thin corpus callosum with brain hypomyelination in all. Follow-up MRI scans in three patients revealed progressive moderate brain shrinkage with leukoencephalopathy. Five patients died within the first 9 years of life and none achieved developmental, communicative or motor skills following birth. These clinical findings are consistent with a developmental brain disorder that begins in the prenatal brain, prevents neural connections from reaching the expected stages at birth, and follows a progressive course. DMXL2 is highly expressed in the brain and at synaptic terminals, regulates v-ATPase assembly and activity and participates in intracellular signalling pathways; however, its functional role is far from complete elucidation. Expression analysis in patient-derived skin fibroblasts demonstrated absence of the DMXL2 protein, revealing a loss of function phenotype. Patients' fibroblasts also exhibited an increased LysoTracker® signal associated with decreased endolysosomal markers and degradative processes. Defective endolysosomal homeostasis was accompanied by impaired autophagy, revealed by lower LC3II signal, accumulation of polyubiquitinated proteins, and autophagy receptor p62, with morphological alterations of the autolysosomal structures on electron microscopy. Altered lysosomal homeostasis and defective autophagy were recapitulated in Dmxl2-silenced mouse hippocampal neurons, which exhibited impaired neurite elongation and synaptic loss. Impaired lysosomal function and autophagy caused by biallelic DMXL2 mutations affect neuronal development and synapse formation and result in Ohtahara syndrome with profound developmental impairment and reduced life expectancy.

Magnetic resonance-guided focused ultrasound thalamotomy for essential tremor: a 5-year single-center experience.

OBJECTIVE: The authors report their experience in treating patients suffering from medication-resistant essential tremor (ET) with MR-guided focused ultrasound (MRgFUS) thalamotomy over a 5-year period. METHODS: Forty-four ET patients treated with unilateral MRgFUS ventral intermediate nucleus (VIM) thalamotomy were assessed using the Clinical Rating Scale for Tremor (CRST) score and the Quality of Life in Essential Tremor Questionnaire (QUEST) over a 5-year span. RESULTS: Tremor was significantly improved immediately following MRgFUS in all patients and ceased completely in 24 patients. CRST scores in the treated hand at baseline (median 19; range 7-32, 44 patients) improved by a median of 16 at 1 month (44 patients; p < 0.0001), 17 at 6 months (31 patients; p < 0.0001), 15 at 1 year (24 patients; p < 0.0001), 18 at 2 years (15 patients; p < 0.0001), 19 at 3 years, (10 patients; p < 0.0001), 21 at 4 years (6 patients; p < 0.01), and 23 at 5 years (2 patients, significance not tested). Return of tremor that impacted activities of daily living was reported in 5 patients (11%). QUEST scores showed significant improvement, with median change of 35 points (p < 0.0001; 44 patients) at 1 month, 33 (p < 0.0001; 31 patients) at 6 months, 27 (p < 0.0001; 24 patients) at 1 year, 26 (p < 0.001; 15 patients) at 2 years, 25 (p < 0.001; 10 patients) at 3 years, 33 (p < 0.001; 6 patients) at 4 years, and 28 (significance not tested, 2 patients) at 5 years. Adverse events after the procedure were reversible in all but 5 patients (11%). CONCLUSIONS: MRgFUS thalamotomy for ET is an effective and safe procedure that provides long-term tremor relief and improvement in quality of life even in patients with medication-resistant disabling tremor. Additional studies with a larger group of patients is needed to substantiate these favorable results.

[EFFECT OF GENDER ON OUTCOME OF TREATMENT FOR TREMOR WITH MRI GUIDED FOCUSED ULTRASOUND].

INTRODUCTION: Thalamotomy is an effective treatment for medication-resistant tremor. MRI-guided focused ultrasound (MRgFUS) has been shown to be an effective and safe treatment for alleviating tremor. OBJECTIVES: We examined whether there is a gender difference in the efficacy and safety of thalamotomy using MRgFUS. METHODS: Seventy patients with moderate to severe medication-resistant tremor were treated with MRgFUS at Rambam Medical Center. Thermal ablation with ultrasound waves was carried out in the MRI suite while real-time monitoring of treatment efficacy and adverse events were recorded. A comparison was made between outcomes in men and women. RESULTS: Seventy patients, 47 men and 23 women with essential tremor, Parkinson's disease, paraneoplastic syndrome, and multiple system atrophy were treated. Both men and women reported the disappearance of tremor after MRgFUS with the exception of one patient with a paraneoplastic syndrome. In all patients, there was a significant decrease in the tremor scores (p <0.001), with no gender difference, and all patients reported a significant improvement in quality of life (p<0.001) regardless of gender. In ten patients, 8 men and 2 women, the tremor returned, but was bothersome in only 4, all men. This gender difference was not statistically significant. Transient adverse events were observed in the same frequency in men and women. The most common adverse event was transient gait instability and ataxia. CONCLUSIONS: In this series of patients, MRgFUS was an effective and safe treatment for both sexes with no significant difference in efficacy or adverse events.

Severe infantile epileptic encephalopathy associated with D-glyceric aciduria: report of a novel case and review.

D-glycerate 2 kinase (DGK) is an enzyme that mediates the conversion of D-glycerate, an intermediate metabolite of serine and fructose metabolism, to 2-phosphoglycerate. Deficiency of DGK leads to accumulation of D-glycerate in various tissues and its massive excretion in urine. D-glyceric aciduria (DGA) is an autosomal recessive metabolic disorder caused by mutations in the GLYCTK gene. The clinical spectrum of DGA is highly variable, ranging from severe progressive infantile encephalopathy to a practically asymptomatic condition. We describe a male patient from a consanguineous Arab family with infantile onset of DGA, characterized by profound psychomotor retardation, progressive microcephaly, intractable seizures, cortical blindness and deafness. Consecutive brain MR imaging showed an evolving brain atrophy, thinning of the corpus callosum and diffuse abnormal white matter signals. Whole exome sequencing identified the homozygous missense variant in the GLYCTK gene [c.455 T > C, NM_145262.3], which affected a highly conserved leucine residue located at a domain of yet unknown function of the enzyme [p.Leu152Pro, NP_660305]. In silico analysis of the variant supported its pathogenicity. A review of the 15 previously reported patients, together with the current one, confirms a clear association between DGA and severe neurological impairment. Yet, future studies of additional patients with DGA are required to better understand the clinical phenotype and pathogenesis.

Two separate functions of NME3 critical for cell survival underlie a neurodegenerative disorder.

We report a patient who presented with congenital hypotonia, hypoventilation, and cerebellar histopathological alterations. Exome analysis revealed a homozygous mutation in the initiation codon of the NME3 gene, which encodes an NDP kinase. The initiation-codon mutation leads to deficiency in NME3 protein expression. NME3 is a mitochondrial outer-membrane protein capable of interacting with MFN1/2, and its depletion causes dysfunction in mitochondrial dynamics. Consistently, the patient's fibroblasts were characterized by a slow rate of mitochondrial dynamics, which was reversed by expression of wild-type or catalytic-dead NME3. Moreover, glucose starvation caused mitochondrial fragmentation and cell death in the patient's cells. The expression of wild-type and catalytic-dead but not oligomerization-attenuated NME3 restored mitochondrial elongation. However, only wild-type NME3 sustained ATP production and viability. Thus, the separate functions of NME3 in mitochondrial fusion and NDP kinase cooperate in metabolic adaptation for cell survival in response to glucose starvation. Given the critical role of mitochondrial dynamics and energy requirements in neuronal development, the homozygous mutation in NME3 is linked to a fatal mitochondrial neurodegenerative disorder.

MRI in predicting conversion to multiple sclerosis within 1 year.

OBJECTIVES: Most patients diagnosed with multiple sclerosis (MS) present with a clinically isolated syndrome (CIS). We aimed to verify previously reported imaging and clinical findings, and to identify new MRI findings that might serve as prognostic factors for a second clinical episode or a change in the MRI scan during the first year following a CIS. MATERIALS AND METHODS: We identified from our medical records, 46 individuals who presented with an episode of CIS, which was followed clinically and with imaging studies. A neuroradiologist blinded to the clinical data reviewed the images and recorded the number of lesions, lesion location, and the largest longitudinal diameter of the lesion. RESULTS: One year after the first MRI, 25 (54%) patients had progressed to MS. The clinical presentation of those who were and were not diagnosed with MS was predominantly motor or sensory deficit. Patients with lesions that were temporal, occipital, or perpendicular to the corpus callosum at the first episode were more likely to have recurrence. Individuals with a combination of more than 13 lesions, with maximal lesion length greater than 0.75 cm, and a lesion perpendicular to the corpus callosum, had a 19 times higher chance of conversion MS during the following year. CONCLUSIONS: Assessment of the number of lesions, lesion location, and maximal lesion size can predict the risk to develop another clinical episode or a new lesion/new enhancement in MRI during the year after CIS. For patients with a higher risk of recurrence, we recommend closer follow-up.