Expanding the phenotype of UPF3B-related disorder: Case reports and literature review.

UPF3B encodes the Regulator of nonsense transcripts 3B protein, a core-member of the nonsense-mediated mRNA decay pathway, protecting the cells from the potentially deleterious actions of transcripts with premature termination codons. Hemizygous variants in the UPF3B gene cause a spectrum of neuropsychiatric issues including intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, and schizophrenia/childhood-onset schizophrenia (COS). The number of patients reported to date is very limited, often lacking an extensive phenotypical and neuroradiological description of this ultra-rare syndrome. Here we report three subjects harboring UPF3B variants, presenting with variable clinical pictures, including cognitive impairment, central hypotonia, and syndromic features. Patients 1 and 2 harbored novel UPF3B variants-the p.(Lys207*) and p.(Asp429Serfs*27) ones, respectively-while the p.(Arg225Lysfs*229) variant, identified in Patient 3, was already reported in the literature. Novel features in our patients are represented by microcephaly, midface hypoplasia, and brain malformations. Then, we reviewed pertinent literature and compared previously reported subjects to our cases, providing possible insights into genotype-phenotype correlations in this emerging condition. Overall, the detailed phenotypic description of three patients carrying UPF3B variants is useful not only to expand the genotypic and phenotypic spectrum of UPF3B-related disorders, but also to ameliorate the clinical management of affected individuals.

Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours.

BACKGROUND: Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. We assessed the safety, tolerability, pharmacokinetics, and preliminary efficacy of berzosertib plus cisplatin. METHODS: Adult patients with advanced solid tumours refractory or resistant to standard of care therapies received ascending doses of cisplatin (day 1) and berzosertib (days 2 and 9) every 3 weeks (Q3W). RESULTS: Thirty-one patients received berzosertib (90-210 mg/m2) and cisplatin (40-75 mg/m2) across seven dose levels. The most common grade ≥3 treatment-emergent adverse events were neutropenia (20.0%) and anaemia (16.7%). There were two dose-limiting toxicities: a grade 3 hypersensitivity reaction and a grade 3 increase in alanine aminotransferase. Berzosertib 140 mg/m2 (days 2 and 9) and cisplatin 75 mg/m2 (day 1) Q3W was determined as the recommended Phase 2 dose. Cisplatin had no apparent effect on berzosertib pharmacokinetics. Of the 31 patients, four achieved a partial response (two confirmed and two unconfirmed) despite having previously experienced disease progression following platinum-based chemotherapy. CONCLUSIONS: Berzosertib plus cisplatin is well tolerated and shows preliminary clinical activity in patients with advanced solid tumours, warranting further evaluation in a Phase 2 setting. CLINICAL TRIALS IDENTIFIER: NCT02157792.

Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours.

BACKGROUND: Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class inhibitor of ataxia telangiectasia and Rad3-related protein kinase (ATR). We assessed multiple ascending doses of berzosertib + gemcitabine ± cisplatin in patients with resistant/refractory advanced solid tumours. METHODS: We evaluated the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of intravenous berzosertib + gemcitabine ± cisplatin using a standard 3 + 3 dose-escalation design. The starting doses were berzosertib 18 mg/m2, gemcitabine 875 mg/m2 and cisplatin 60 mg/m2. RESULTS: Fifty-two patients received berzosertib + gemcitabine and eight received berzosertib + gemcitabine + cisplatin. Four patients receiving berzosertib + gemcitabine had a total of seven dose-limiting toxicities (DLTs) and three receiving berzosertib + gemcitabine + cisplatin had a total of three DLTs. Berzosertib 210 mg/m2 (days 2 and 9) + gemcitabine 1000 mg/m2 (days 1 and 8) Q3W was established as the recommended Phase 2 dose (RP2D); no RP2D was determined for berzosertib + gemcitabine + cisplatin. Neither gemcitabine nor cisplatin affected berzosertib PK. Most patients in both arms achieved a best response of either partial response or stable disease. CONCLUSIONS: Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs. CLINICAL TRIAL IDENTIFIER: NCT02157792.

Nerve biopsy: Current indications and decision tools.

After initial investigation of patients presenting with symptoms suggestive of neuropathy, a clinical decision is made for a minority of patients to undergo further assessment with nerve biopsy. Many nerve biopsies do not demonstrate a definitive pathological diagnosis and there is considerable cost and morbidity associated with the procedure. This highlights the need for appropriate selection of patients, nerves and neuropathology techniques. Additionally, concomitant muscle and skin biopsies may improve the diagnostic yield in some cases. Several advances have been made in diagnostics in recent years, particularly in genomics. The indications for nerve biopsy have consequently changed over time. This review explores the current indications for nerve biopsies and some of the issues surrounding its use. Also included are comments on alternative diagnostic modalities that may help to supplant or reduce the use of nerve biopsy as a diagnostic test. These primarily include extraneural biopsy and neuroimaging techniques such as magnetic resonance neurography and nerve ultrasound. Finally, we propose an algorithm to assist in deciding when to perform nerve biopsies.

A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations.

A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.

Trends in oral anticoagulant co-prescription with antiepileptic drugs among adults with epilepsy, 2010-2018.

Treatment considerations for epilepsy patients requiring anticoagulation are changing, and actual prescribing practices have not been characterized. We used the 2010-2018 Optum Clinformatics® Data Mart Database to estimate the annual prevalence and distinguish the patterns of oral anticoagulants (OACs) co-dispensed with antiepileptic drugs (AEDs) among adults with epilepsy. Monotonic trends were assessed using the Spearman rank correlation coefficient (ρ). Multivariable logistic regression models were built to evaluate the associations of sociodemographic characteristics. Among 345,892 adults with epilepsy (56.5% female; median age 61, IQR 46-74) on studied AEDs, the prevalence per thousand of concurrent OACs increased from 58.4 in 2010 to 92.0 in 2018 (OR 1.63, CI 1.58-1.69). Direct-acting oral anticoagulant (DOAC) use rapidly increased from 2010 to 2018 (ρ = 1.00; P < 0.001), with a corresponding decrease in warfarin use (ρ = -0.97; P < 0.001). Among OAC/AED dispensings in 2018, warfarin was more likely to be co-dispensed with potentially interacting, enzyme-inducing antiepileptic drugs (EI-AEDs) versus presumably non-interacting, non-enzyme inducing antiepileptic drugs (OR 1.48, CI 1.38-1.59). Characteristics independently associated with concurrent OAC/EI-AED use included younger age, female sex, white race, net worth <$250 K, and lower education levels. Our findings demonstrate the expanding use and evolving patterns of OAC/AED co-dispensing, and ensuing critical need to further understanding regarding postulated interactions.

Inhaled alprazolam rapidly suppresses epileptic activity in photosensitive participants.

OBJECTIVE: Treatment options for seizure clusters are limited; the need for easy-to-administer treatments remains. The Staccato system delivers drug deep into the lung via inhalation. In this phase 2a study, we investigated the ability of three different doses of Staccato alprazolam to suppress the electroencephalographic (EEG) photoparoxysmal response (PPR) compared with placebo in participants with photosensitive seizures. METHODS: Adults (18-60 years) with a diagnosis and history of PPR on EEG with or without an epilepsy diagnosis were eligible to participate. Participants received Staccato alprazolam 0.5, 1.0, and 2.0 mg, and Staccato placebo (twice) in random order. Intermittent photic stimulation and clinical assessments were performed at one predose and seven postdose time points. The primary endpoint of the study was the change in standardized photosensitivity range (SPR) in participants receiving each dose of Staccato alprazolam. RESULTS: Fifteen participants with a prior epilepsy diagnosis were screened; five were enrolled, randomized, and completed the study. All participants were white females with a mean (SD) age of 27.2 (6.8) years. All doses of Staccato alprazolam reduced the SPR at 2 minutes; the effect was sustained through 4 hours for the 0.5-mg dose and 6 hours for the 1.0- and 2.0-mg doses. The magnitude and duration of sedation and sleepiness were dose-related. Four participants (80%) experienced ≥1 adverse event (AE); none was severe or serious. Cough, diarrhea, dysgeusia, oral dysesthesia, sedation, and somnolence were experienced by two participants (40%) each. SIGNIFICANCE: This proof-of-concept study demonstrated that Staccato alprazolam 0.5, 1.0, and 2.0 mg rapidly suppressed epileptiform activity in photosensitive participants with epilepsy. The AE profile of Staccato alprazolam was similar to what has been reported for alprazolam for other indications. The results support further development of Staccato alprazolam as a rescue medication for the acute treatment of seizures.

Vasculitic neuropathy: Comparison of clinical predictors with histopathological outcome.

INTRODUCTION: To improve diagnostic accuracy, in this study we compared prebiopsy clinical parameters with subsequent pathological confirmation of peripheral nerve vasculitis. METHODS: Clinical, laboratory, and neurophysiological parameters were analyzed for consecutive patients referred for nerve biopsy with suspected vasculitis. Patients were assigned pathological categories of definite, probable, possible, or absent vasculitis using validated guidelines. Patients with definite or probable vasculitis were considered to have pathologically confirmed vasculitis. RESULTS: From a cohort of 78 patients, biopsy confirmed vasculitis in 29.5%. Parameters that best differentiated between pathologically confirmed and pathologically unlikely vasculitis were stepwise clinical progression (34.8% vs. 5.6%), the presence of serum anti-myeloperoxidase antibody (28.6% vs. 2.2%) and rheumatoid factor seropositivity (38.1% vs. 10.7%). Pathologically absent vasculitis was frequent in patients with normal (100%) or primarily demyelinating (87.5%) nerve conduction studies. DISCUSSION: Factoring the negative predictors of pathologically confirmed vasculitis into decision-making can reduce the frequency of diagnostically unhelpful nerve biopsies. Muscle Nerve 59:643-649, 2019.

New 4-Amino-1,2,3-Triazole Inhibitors of Indoleamine 2,3-Dioxygenase Form a Long-Lived Complex with the Enzyme and Display Exquisite Cellular Potency.

Indoleamine-2,3 dioxygenase 1 (IDO1) has emerged as a central regulator of immune responses in both normal and disease biology. Due to its established role in promoting tumour immune escape, IDO1 has become an attractive target for cancer treatment. A novel series of highly cell potent IDO1 inhibitors based on a 4-amino-1,2,3-triazole core have been identified. Comprehensive kinetic, biochemical and structural studies demonstrate that compounds from this series have a noncompetitive kinetic mechanism of action with respect to the tryptophan substrate. In co-complex crystal structures, the compounds bind in the tryptophan pocket and make a direct ligand interaction with the haem iron of the porphyrin cofactor. It is proposed that these data can be rationalised by an ordered-binding mechanism, in which the inhibitor binds an apo form of the enzyme that is not competent to bind tryptophan. These inhibitors also form a very tight, long-lived complex with the enzyme, which partially explains their exquisite cellular potency. This novel series represents an attractive starting point for the future development of potent IDO1-targeted drugs.

Neurofascin-155 IGG4 Neuropathy: Pathophysiological Insights, Spectrum of Clinical Severity and Response To treatment.

INTRODUCTION: Sensorimotor neuropathy associated with IgG4 antibodies to neurofascin-155 (NF155) was recently described. The clinical phenotype is typically associated with young onset, distal weakness, and in some cases, tremor. METHODS: From a consecutive cohort of 55 patients diagnosed with chronic inflammatory demyelinating polyneuropathy, screening for anti-NF155 antibodies was undertaken. Patients underwent clinical assessment, diagnostic neurophysiology, including peripheral axonal excitability studies and nerve ultrasound. RESULTS: Three of 55 chronic inflammatory demyelinating polyneuropathy patients (5%) tested positive for anti-NF155 IgG4. Patients presenting with more severe disease had higher antibody titers. Ultrasound demonstrated diffuse nerve enlargement. Axonal excitability studies were markedly abnormal, with subsequent mathematical modeling of the results supporting disruption of the paranodal seal. DISCUSSION: A broad spectrum of disease severity and treatment response may be observed in anti-NF155 neuropathy. Excitability studies support the pathogenic role of anti-NF155 IgG4 antibodies targeting the paranodal region. Muscle Nerve 57: 848-851, 2018.

The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews.

PURPOSE OF REVIEW: Pharmaceutical cannabinoids such as nabiximols, nabilone and dronabinol, and plant-based cannabinoids have been investigated for their therapeutic potential in treating multiple sclerosis (MS) symptoms. This review of reviews aimed to synthesise findings from high quality systematic reviews that examined the safety and effectiveness of cannabinoids in multiple sclerosis. We examined the outcomes of disability and disability progression, pain, spasticity, bladder function, tremor/ataxia, quality of life and adverse effects. RECENT FINDINGS: We identified 11 eligible systematic reviews providing data from 32 studies, including 10 moderate to high quality RCTs. Five reviews concluded that there was sufficient evidence that cannabinoids may be effective for symptoms of pain and/or spasticity in MS. Few reviews reported conclusions for other symptoms. Recent high quality reviews find cannabinoids may have modest effects in MS for pain or spasticity. Future research should include studies with non-cannabinoid comparators; this is an important gap in the evidence.

Addressing barriers to surgical evaluation for patients with epilepsy.

OBJECTIVE: Patients with poorly controlled seizures are at elevated risk of epilepsy-related morbidity and mortality. For patients with drug-resistant epilepsy that is focal at onset, epilepsy surgery is the most effective treatment available and offers a 50-80% cure rate. Yet, it is estimated that only 1% of patients with drug-resistant epilepsy undergo surgery in a timely fashion, and delays to surgery completion are considerable. The aim of this study was to increase availability and decrease delay of surgical evaluation at our epilepsy center for patients with drug-resistant epilepsy by removing process barriers. METHODS: For this quality improvement (QI) initiative, we convened a multidisciplinary team to construct a presurgical pathway process map and complete root cause analysis. This inquiry revealed that the current condition allowed patients to proceed through the pathway without centralized oversight. Therefore, we appointed an epilepsy surgery nurse manager, and under her direction, multiple additional process improvement interventions were applied. We then retrospectively compared preintervention (2014-2015) and postintervention (2016-2017) cohorts of patient undergoing the presurgical pathway. The improvement measures were patient throughput and pathway sojourn times. As a balancing measure, we considered the proportion of potentially eligible patients (epilepsy monitoring unit (EMU) admissions) who ultimately completed epilepsy surgery. RESULTS: Following our intervention, patient throughput was substantially increased for each stage of the presurgical pathway (32%-96% growth). However, patient sojourn times were not improved overall. No difference was observed in the proportion of possible candidates who ultimately completed epilepsy surgery. SIGNIFICANCE: Although process improvement expanded the number of patients who underwent epilepsy surgical evaluation, we experienced concurrent prolongation of the time from pathway initiation to completion. Ongoing improvement cycles will focus on newly identified residual sources of bottleneck and delay.

Differentiating lower motor neuron syndromes.

Lower motor neuron (LMN) syndromes typically present with muscle wasting and weakness and may arise from pathology affecting the distal motor nerve up to the level of the anterior horn cell. A variety of hereditary causes are recognised, including spinal muscular atrophy, distal hereditary motor neuropathy and LMN variants of familial motor neuron disease. Recent genetic advances have resulted in the identification of a variety of disease-causing mutations. Immune-mediated disorders, including multifocal motor neuropathy and variants of chronic inflammatory demyelinating polyneuropathy, account for a proportion of LMN presentations and are important to recognise, as effective treatments are available. The present review will outline the spectrum of LMN syndromes that may develop in adulthood and provide a framework for the clinician assessing a patient presenting with predominantly LMN features.

Incidence and prevalence of NMOSD in Australia and New Zealand.

OBJECTIVES: We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry. BACKGROUND: NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established. METHODS: Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases. RESULTS: NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD. CONCLUSIONS: NMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry.

Detection of generalized tonic-clonic seizures using surface electromyographic monitoring.

OBJECTIVE: A prospective multicenter phase III trial was undertaken to evaluate the performance and tolerability in the epilepsy monitoring unit (EMU) of an investigational wearable surface electromyographic (sEMG) monitoring system for the detection of generalized tonic-clonic seizures (GTCSs). METHODS: One hundred ninety-nine patients with a history of GTCSs who were admitted to the EMU in 11 level IV epilepsy centers for clinically indicated video-electroencephalographic monitoring also received sEMG monitoring with a wearable device that was worn on the arm over the biceps muscle. All recorded sEMG data were processed at a central site using a previously developed detection algorithm. Detected GTCSs were compared to events verified by a majority of three expert reviewers. RESULTS: For all subjects, the detection algorithm detected 35 of 46 (76%, 95% confidence interval [CI] = 0.61-0.87) of the GTCSs, with a positive predictive value (PPV) of 0.03 and a mean false alarm rate (FAR) of 2.52 per 24 h. For data recorded while the device was placed over the midline of the biceps muscle, the system detected 29 of 29 GTCSs (100%, 95% CI = 0.88-1.00), with a detection delay averaging 7.70 s, a PPV of 6.2%, and a mean FAR of 1.44 per 24 h. Mild to moderate adverse events were reported in 28% (55 of 199) of subjects and led to study withdrawal in 9% (17 of 199). These adverse events consisted mostly of skin irritation caused by the electrode patch that resolved without treatment. No serious adverse events were reported. SIGNIFICANCE: Detection of GTCSs using an sEMG monitoring device on the biceps is feasible. Proper positioning of this device is important for accuracy, and for some patients, minimizing the number of false positives may be challenging.

Axonal damage in central and peripheral nervous system inflammatory demyelinating diseases: common and divergent pathways of tissue damage.

PURPOSE OF REVIEW: Axonal injury is the pathological correlate of fixed disability in the inflammatory demyelinating disorders of the central and peripheral nervous system. The mechanisms that initiate and propagate neurodegeneration in these conditions are poorly understood, and a lack of available neuroprotective and proreparative therapies represent a significant unmet clinical need. In this article, we review new data pertaining to the convergent and divergent immunological, cellular, and molecular mechanisms that underpin neurodegeneration in multiple sclerosis and the chronic inflammatory demyelinating neuropathies that will inform the development of targeted therapies. RECENT FINDINGS: New insights have been gained from recognition of the axon as an integral component of the axon-myelin unit, identification of defects in axonal transport, elucidation of mechanisms of Wallerian degeneration and, in the central nervous system, the appreciation of trans-synaptic axonal degeneration, and widespread cortical synaptopathy. Concurrently, specific immune triggers of axonal injury, particularly in the peripheral immune system; and inhibitors of repair and regrowth, have been identified. SUMMARY: Neurodegeneration is a critical determinant of disability in the inflammatory demyelinating diseases of both the central nervous system and peripheral nervous system. Current therapies are restricted to agents that (effectively) treat the inflammatory components of these conditions. Although propagated, and in some instances triggered, by inflammation, axon damage will in future years be treated or prevented with adjuvant, targeted therapies that exploit emerging pathways to neurodegeneration.

Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory neuropathy, classically characterised by a slowly progressive onset and symmetrical, sensorimotor involvement. However, there are many phenotypic variants, suggesting that CIDP may not be a discrete disease entity but rather a spectrum of related conditions. While the abiding theory of CIDP pathogenesis is that cell-mediated and humoral mechanisms act together in an aberrant immune response to cause damage to peripheral nerves, the relative contributions of T cell and autoantibody responses remain largely undefined. In animal models of spontaneous inflammatory neuropathy, T cell responses to defined myelin antigens are responsible. In other human inflammatory neuropathies, there is evidence of antibody responses to Schwann cell, compact myelin or nodal antigens. In this review, the roles of the cellular and humoral immune systems in the pathogenesis of CIDP will be discussed. In time, it is anticipated that delineation of clinical phenotypes and the underlying disease mechanisms might help guide diagnostic and individualised treatment strategies for CIDP.

A new era in the treatment of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system with a multifactorial aetiology and highly variable natural history. A growing understanding of the immunopathogenesis of the condition has led to an expanding array of therapies for this previously untreatable disease. While a cure for MS remains elusive, the potential to reduce inflammatory disease activity by preventing relapses and minimising disease progression is achievable. The importance of early treatment in minimising long-term disability is increasingly recognised. Most of the newer, more effective therapies are associated with risks and practical problems that necessitate an active management strategy and continuous vigilance. While the initiation of these therapies is likely to remain the responsibility of neurologists, other specialist physicians and general practitioners will be involved in the identification and management of adverse effects.