Huntingtin-lowering strategies in Huntingon's disease: Antisense oligonucleotides, small RNAs, and gene editing

The idea to lower mutant huntingtin is especially appealing in Huntington's disease (HD). It is autosomal dominant, so that expression of the mutant allele causes the disease. Advances in RNA and gene regulation provide foundations for the huntingtin gene (both normal and mutant alleles) and possibly the mutant allele only. There is much preclinical animal work to support the concept of gene and RNA silencing, but, to date, no clinical studies have been attempted in HD. Preventing expression of mutant huntingtin protein is at the cusp for a human trial. Antisense oligonucleotides delivered to patients with amyotrophic lateral sclerosis have been well tolerated; small RNAs administered to rodent and nonhuman primate brain knocked down huntingtin messenger RNA (mRNA); short-hairpin complementary DNA of microRNAs can be expressed in adeno-associated virus to provide long-term silencing of huntingtin mRNA and protein. We expect that these approaches will be ready for clinical studies in the near future, once safety has been validated. Our understanding of gene editing—changing the huntingtin gene itself—is rapidly progressing. Harnessing our knowledge of transcription and translation should push scientific creativity to new and exciting advances that overcome the lethality of the mutant gene in HD

Movement Disorders 2014

Current therapeutic options for Huntington's disease: Good clinical practice versus evidence-based approaches?

Therapeutic decision-making in Huntington's disease (HD) is often guided by clinical experience, because of the limited empirical evidence available. The only medication for HD that has met the regulatory hurdle for approval is tetrabenazine, indicated for the treatment of chorea. However, its use has limitations, and in the setting of specific contraindications or comorbidities the treatment of choice for chorea is still the multipurpose antipsychotics. For the management of psychiatric disturbances, selective serotonin reuptake inhibitors (SSRIs) and mood stabilizers are often used, although empirical evidence is lacking. Finally, no known effective treatment is available for cognitive dysfunction in HD. We discuss the limited evidence available and current expert opinion on medical treatment of the dominant motor, psychiatric, and cognitive features of HD. This follows a brief introduction on the general principles of HD management and on evidence-based medicine in relation to clinical practice

Movement Disorders 2014

Long-term safety and efficacy of zonisamide versus carbamazepine monotherapy for treatment of partial seizures in adults with newly diagnosed epilepsy: Results of a phase III, randomized, double-blind study

Objective

To investigate the long-term safety and maintenance of efficacy of monotherapy with once-daily zonisamide versus twice-daily controlled-release carbamazepine for partial seizures in adults with newly diagnosed epilepsy.

Methods

Long-term, double-blind, extension study, conducted in patients completing a phase III noninferiority trial comparing zonisamide and carbamazepine monotherapy. Patients continued their randomized treatment, with dosing adjusted according to tolerability/response (zonisamide 200–500 mg/day; carbamazepine 400–1,200 mg/day). Safety assessments included treatment-emergent adverse events (TEAEs) and clinical laboratory parameters. Efficacy assessments included retention rate and the proportion of patients remaining seizure free for ≥24 months.

Results

Overall, 120 (87.6%) of 137 patients randomized to zonisamide and 134 (84.8%) of 158 patients randomized to carbamazepine completed the study. More than three-fourths of patients were exposed to >24 months of treatment. For zonisamide versus carbamazepine, incidences were similar for TEAEs (52.6% vs. 46.2%), serious treatment-related TEAEs (0.7% vs. 1.9%), and TEAEs leading to withdrawal (1.5% vs. 0.6%). The incidence of treatment-related TEAEs was 26.3% for zonisamide compared with 19.6% for carbamazepine, and the most frequently reported treatment-related TEAEs were decreased weight (5.1% vs. 0%), decreased appetite (3.6% vs. 0%), memory impairment (2.9% vs. 3.2%), and decreased hemoglobin level (1.5% vs. 3.2%). Most TEAEs were of mild or moderate intensity. There were no reports of Stevens-Johnson syndrome or toxic epidermal necrolysis in either group. Zonisamide was associated with small-to-moderate decreases in bicarbonate levels from baseline (mean −3.4 mm). There were no reports of metabolic acidosis. Retention rates were generally similar between treatment groups at all time points throughout the extension study. The proportion of patients remaining seizure free for ≥24 months was also similar for zonisamide (32.3%) and carbamazepine (35.2%).

Significance

Once-daily zonisamide monotherapy demonstrated favorable long-term safety and maintenance of efficacy in treating partial seizures in adults with newly diagnosed epilepsy. No new or unexpected safety findings emerged.

Epilepsia 2014

Accuracy of Brain Amyloid Detection in Clinical Practice Using Cerebrospinal Fluid β-Amyloid 42 A Cross-Validation Study Against Amyloid Positron Emission Tomography

Importance  Before adding cerebrospinal fluid (CSF) biomarkers to the diagnostic workup of Alzheimer disease, it needs to be determined whether CSF biomarkers analyzed in routine clinical practice can reliably predict cortical β-amyloid (Aβ) deposition.

Objectives  To study whether CSF biomarkers, analyzed consecutively in routine clinical practice during 2 years, can predict cortical Aβ deposition and to establish a threshold for Aβ42 abnormality.

Design, Setting, and Participants  This cross-sectional study (The Swedish BioFINDER [Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably] Study) was conducted at 3 memory clinics. It involved consecutively referred, nondemented patients with mild cognitive symptoms (original cohort, n = 118; validation cohort, n = 38).

Exposures  Amyloid positron emission tomography imaging with 18F-flutemetamol.

Main Outcomes and Measures  Analyses of CSF Aβ42, total tau, and phosphorylated tau using an enzyme-linked immunosorbent assay (INNOTEST) in clinical samples.

Results  The agreement between Aβ classification with CSF Aβ42 and 18F-flutemetamol positron emission tomography was very high (κ = 0.85). Of all the cases, 92% were classified identically using an Aβ42 cutoff of 647 pg/mL or less. Cerebrospinal fluid Aβ42 predicted abnormal cortical Aβ deposition accurately (odds ratio, 165; 95% CI, 39-693; area under the receiver operating characteristic curve, 0.94; 95% CI, 0.88-0.97). The association was independent of age, sex, APOE(apolipoprotein E) genotype, hippocampal volume, memory, and global cognition (adjusted odds ratio, 169; 95% CI, 25-1143). Using ratios of CSF Aβ42:tau or Aβ42:phosphorylated tau did not improve the prediction of Aβ deposition. Cerebrospinal fluid Aβ42 correlated significantly with Aβ deposition in all cortical regions. The highest correlations were in regions with high 18F-flutemetamol retention (eg, posterior cingulum and precuneus, r = −0.72). 18F-flutemetamol retention, but not CSF Aβ42, correlated significantly with global cognition (r = −0.32), memory function (r = −0.28), and hippocampal volume (r = −0.36) among those with abnormal Aβ deposition. Finally, the CSF Aβ42 cutoff derived from the original cohort (≤647 pg/mL) had an equally high agreement (95%; κ = 0.89) with 18F-flutemetamol positron emission tomography in the validation cohort.

Conclusions and Relevance  Cerebrospinal fluid Aβ42 analyzed consecutively in routine clinical practice at an accredited laboratory can be used with high accuracy to determine whether a patient has normal or increased cortical Aβ deposition and so can be valuable for the early diagnosis of Alzheimer disease. Abnormal 18F-flutemetamol retention levels correlate with disease stage in patients with mild cognitive symptoms, but this is not the case for CSF Aβ42 measurements.

JAMA Neurology 2014

Effect of Advancing Age on Outcomes of Deep Brain Stimulation for Parkinson Disease

Importance  Deep brain stimulation (DBS) is a well-established modality for the treatment of advanced Parkinson disease (PD). Recent studies have found DBS plus best medical therapy to be superior to best medical therapy alone for patients with PD and early motor complications. Although no specific age cutoff has been defined, most clinical studies have excluded patients older than 75 years of age. We hypothesize that increasing age would be associated with an increased number of postoperative complications.

Objective  To evaluate the stepwise effect of increasing age (in 5-year epochs) on short-term complications following DBS surgery.

Design, Setting, and Participants  A large, retrospective cohort study was performed using the Thomson Reuters MarketScan national database that examined 1757 patients who underwent DBS for PD during the period from 2000 to 2009.

Main Outcomes and Measures  Primary measures examined included hospital length of stay and aggregate and individual complications within 90 days following surgery. Multivariate logistic regression analysis was used to calculate complication-related odds ratios (ORs) for each 5-year age epoch after controlling for covariates.

Results  Overall, 132 of 1757 patients (7.5%) experienced at least 1 complication within 90 days, including wound infections (3.6%), pneumonia (2.3%), hemorrhage or hematoma (1.4%), or pulmonary embolism (0.6%). After adjusting for covariates, we found that increasing age (ranging from <50 to 90 years of age) did not significantly affect overall 90-day complication rates (OR, 1.10 per 5-year increase [95% CI, 0.96-1.25]; P = .17). The 2 most common procedure-related complications, hemorrhage (OR, 0.82 [95% CI, 0.63-1.07]; P = .14) and infection (OR, 1.04 [95% CI, 0.87-1.24]; P = .69), did not significantly increase with age.

Conclusions and Relevance  Older patients with PD (>75 years) who were selected to undergo DBS surgery showed a similar 90-day complication risk (including postoperative hemorrhage or infection) compared with younger counterparts. Our findings suggest that age alone should not be a primary exclusion factor for determining candidacy for DBS. Instead, a clear focus on patients with medication-refractory and difficult to control on-off fluctuations with preserved cognition, regardless of age, may allow for an expansion of the traditional therapeutic window.

JAMA Neurology 2014

ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism

Two siblings with fatal Leigh disease had increased excretion of S-(2-carboxypropyl)cysteine and several other metabolites that are features of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, a rare defect in the valine catabolic pathway associated with Leigh-like disease. However, this diagnosis was excluded by HIBCH sequencing and normal enzyme activity. In contrast to HIBCH deficiency, the excretion of 3-hydroxyisobutyryl-carnitine was normal in the children, suggesting deficiency of short-chain enoyl-CoA hydratase (ECHS1 gene). This mitochondrial enzyme is active in several metabolic pathways involving fatty acids and amino acids, including valine, and is immediately upstream of HIBCH in the valine pathway. Both children were compound heterozygous for a c.473C > A (p.A158D) missense mutation and a c.414+3G>C splicing mutation in ECHS1. ECHS1 activity was markedly decreased in cultured fibroblasts from both siblings, ECHS1 protein was undetectable by immunoblot analysis and transfection of patient cells with wild-type ECHS1 rescued ECHS1 activity. The highly reactive metabolites methacrylyl-CoA and acryloyl-CoA accumulate in deficiencies of both ECHS1 and HIBCH and are probably responsible for the brain pathology in both disorders. Deficiency of ECHS1 or HIBCH should be considered in children with Leigh disease. Urine metabolite testing can detect and distinguish between these two disorders.

Brain 2014

Mutations in RARS cause hypomyelination.

Hypomyelinating disorders of the central nervous system are still a diagnostic challenge, as many patients remain without genetic diagnosis. Using magnetic resonance imaging (MRI) pattern recognition and whole exome sequencing, we could ascertain compound heterozygous mutations in RARS in 4 patients with hypomyelination. Clinical features included severe spasticity and nystagmus. RARS encodes the cytoplasmic arginyl-tRNA synthetase, an enzyme essential for RNA translation. This protein is among the subunits of the multisynthetase complex, which emerges as a key player in myelination. 

Ann Neurol 2014

Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden

Objectives: In this cross-sectional study, we tested the construct validity of a “total SVD score,” which combines individual MRI features of small-vessel disease (SVD) in one measure, by testing associations with vascular risk factors and stroke subtype.

Methods: We analyzed data from patients with lacunar or nondisabling cortical stroke from 2 prospective stroke studies. Brain MRI was rated for the presence of lacunes, white matter hyperintensities, cerebral microbleeds, and perivascular spaces independently. The presence of each SVD feature was summed in an ordinal “SVD score” (range 0–4). We tested associations with vascular risk factors, stroke subtype, and cerebral atrophy using ordinal regression analysis.

Results: In 461 patients, multivariable analysis found that age (odds ratio [OR] 1.10, 95% confidence interval [CI] 1.08–1.12), male sex (OR 1.58, 95% CI 1.10–2.29), hypertension (OR 1.50, 95% CI 1.02–2.20), smoking (OR 2.81, 95% CI 1.59–3.63), and lacunar stroke subtype (OR 2.45, 95% CI 1.70–3.54) were significantly and independently associated with the total SVD score. The score was not associated with cerebral atrophy.

Conclusions: The total SVD score may provide a more complete estimate of the full impact of SVD on the brain, in a simple and pragmatic way. It could have potential for patient or risk stratification or early efficacy assessment in clinical trials of interventions to prevent SVD progression and may (after further testing) have a useful role in clinical practice.

Neurology 2014

Classification algorithms using multiple MRI features in mild traumatic brain injury

Objective: The purpose of this study was to develop an algorithm incorporating MRI metrics to classify patients with mild traumatic brain injury (mTBI) and controls.

Methods: This was an institutional review board–approved, Health Insurance Portability and Accountability Act–compliant prospective study. We recruited patients with mTBI and healthy controls through the emergency department and general population. We acquired data on a 3.0T Siemens Trio magnet including conventional brain imaging, resting-state fMRI, diffusion-weighted imaging, and magnetic field correlation (MFC), and performed multifeature analysis using the following MRI metrics: mean kurtosis (MK) of thalamus, MFC of thalamus and frontal white matter, thalamocortical resting-state networks, and 5 regional gray matter and white matter volumes including the anterior cingulum and left frontal and temporal poles. Feature selection was performed using minimal-redundancy maximal-relevance. We used classifiers including support vector machine, naive Bayesian, Bayesian network, radial basis network, and multilayer perceptron to test maximal accuracy.

Results: We studied 24 patients with mTBI and 26 controls. Best single-feature classification uses thalamic MK yielding 74% accuracy. Multifeature analysis yields 80% accuracy using the full feature set, and up to 86% accuracy using minimal-redundancy maximal-relevance feature selection (MK thalamus, right anterior cingulate volume, thalamic thickness, thalamocortical resting-state network, thalamic microscopic MFC, and sex).

Conclusion: Multifeature analysis using diffusion-weighted imaging, MFC, fMRI, and volumetrics may aid in the classification of patients with mTBI compared with controls based on optimal feature selection and classification methods.

Classification of evidence: This study provides Class III evidence that classification algorithms using multiple MRI features accurately identifies patients with mTBI as defined by American Congress of Rehabilitation Medicine criteria compared with healthy controls.

Neurology 2014

Discovering rare diseases: Marked efficacy of vemurafenib in suprasellar Erdheim-Chester disease

Erdheim-Chester disease (ECD) is a rare non–Langerhans cell histiocytosis characterized by the accumulation of foamy CD68+CD1a− histiocytes. Tissue infiltration preferentially affects long bones and retroperitoneal and peri-aortic spaces, but almost any organ or system can be affected. Cardiac and neurologic involvements are associated with significantly higher levels of mortality and morbidity.

Neurology 2014

Allodynia and hyperalgesia in neuropathic pain: clinical manifestations and mechanisms

Allodynia (pain due to a stimulus that does not usually provoke pain) and hyperalgesia (increased pain from a stimulus that usually provokes pain) are prominent symptoms in patients with neuropathic pain. Both are seen in various peripheral neuropathies and central pain disorders, and affect 15—50% of patients with neuropathic pain. Allodynia and hyperalgesia are classified according to the sensory modality (touch, pressure, pinprick, cold, and heat) that is used to elicit the sensation. Peripheral sensitisation and maladaptive central changes contribute to the generation and maintenance of these reactions, with separate mechanisms in different subtypes of allodynia and hyperalgesia. Pain intensity and relief are important measures in clinical pain studies, but might be insufficient to capture the complexity of the pain experience. Better understanding of allodynia and hyperalgesia might provide clues to the underlying pathophysiology of neuropathic pain and, as such, they represent new or additional endpoints in pain trials.

Neurology 2014

Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research

The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood—and adolescent—onset multiple sclerosis have been informed by many new insights in the past 7 years. National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis. The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume. Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis. Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed.

Lancet Neurology 2014

The challenge and promise of anti-epileptic therapy development in animal models

Translation of successful target and compound validation studies into clinically effective therapies is a major challenge, with potential for costly clinical trial failures. This situation holds true for the epilepsies—complex diseases with different causes and symptoms. Although the availability of predictive animal models has led to the development of effective antiseizure therapies that are routinely used in clinical practice, showing that translation can be successful, several important unmet therapeutic needs still exist. Available treatments do not fully control seizures in a third of patients with epilepsy, and produce substantial side-effects. No treatment can prevent the development of epilepsy in at-risk patients or cure patients with epilepsy. And no specific treatment for epilepsy-associated comorbidities exists. To meet these demands, a redesign of translational approaches is urgently needed.

Neurology 2014

Adipokines: a link between obesity and dementia?

Being overweight or obese, as measured with body-mass index or central adiposity (waist circumference), and the trajectory of body-mass index over the life course have been associated with brain atrophy, white matter changes, disturbances of blood—brain barrier integrity, and risk of all-cause late-onset dementia and Alzheimer's disease. This observation leads us to question what it is about body-mass index that is associated with health of the brain and dementia risk. If high body-mass index and central adiposity represent an increase in adipose tissue, then the endocrine function of adipose tissue, mediated by adipose tissue hormones and adipokines, could be a clue to mechanisms that underlie the association with dementia and Alzheimer's disease. Hundreds of adipokines have been identified, creating a complexity that is a challenge to simplify. Nonetheless, adipokines are being investigated in association with clinical dementia outcomes, and with imaging-based measures of brain volume, structure, and function in human beings and in preclinical models of clinical dementia.

Lancet Neurology 2014

Impaired Cerebrovascular Reactivity in Multiple Sclerosis

Importance  Cerebrovascular reactivity (CVR) is an inherent indicator of the dilatory capacity of cerebral arterioles for a vasomotor stimulus for maintaining a spontaneous and instant increase of cerebral blood flow (CBF) in response to neural activation. The integrity of this mechanism is essential to preserving healthy neurovascular coupling; however, to our knowledge, no studies have investigated whether there are CVR abnormalities in multiple sclerosis (MS).

Objective  To use hypercapnic perfusion magnetic resonance imaging to assess CVR impairment in patients with MS.

Design, Setting, and Participants  A total of 19 healthy volunteers and 19 patients with MS underwent perfusion magnetic resonance imaging based on pseudocontinuous arterial spin labeling to measure CBF at normocapnia (ie, breathing room air) and hypercapnia. The hypercapnia condition is achieved by breathing 5% carbon dioxide gas mixture, which is a potent vasodilator causing an increase of CBF.

Main Outcomes and Measures  Cerebrovascular reactivity was calculated as the percent increase of normocapnic to hypercapnic CBF normalized by the change in end-tidal carbon dioxide, which was recorded during both conditions. Group analysis was performed for regional and global CVR comparison between patients and controls. Regression analysis was also performed between CVR values, lesion load, and brain atrophy measures in patients with MS.

Results  A significant decrease of mean (SD) global gray matter CVR was found in patients with MS (3.56 [0.81]) compared with healthy controls (5.08 [1.56]; P = .001). Voxel-by-voxel analysis showed diffuse reduction of CVR in multiple regions of patients with MS. There was a significant negative correlation between gray matter CVR and lesion volume (R = 0.6, P = .004) and a significant positive correlation between global gray matter CVR and gray matter atrophy index (R = 0.5, P = .03).

Conclusions and Relevance  Our quantitative imaging findings suggest impairment in functional cerebrovascular pathophysiology, by measuring a diffuse decrease in CVR, which may be the underlying cause of neurodegeneration in MS.

Neurology 2014

Exome Sequencing in the Clinical Diagnosis of Sporadic or Familial Cerebellar Ataxia

Importance  Cerebellar ataxias are a diverse collection of neurologic disorders with causes ranging from common acquired etiologies to rare genetic conditions. Numerous genetic disorders have been associated with chronic progressive ataxia and this consequently presents a diagnostic challenge for the clinician regarding how to approach and prioritize genetic testing in patients with such clinically heterogeneous phenotypes. Additionally, while the value of genetic testing in early-onset and/or familial cases seems clear, many patients with ataxia present sporadically with adult onset of symptoms and the contribution of genetic variation to the phenotype of these patients has not yet been established.

Objective  To investigate the contribution of genetic disease in a population of patients with predominantly adult- and sporadic-onset cerebellar ataxia.

Design, Setting, and Participants  We examined a consecutive series of 76 patients presenting to a tertiary referral center for evaluation of chronic progressive cerebellar ataxia.

Main Outcomes and Measures  Next-generation exome sequencing coupled with comprehensive bioinformatic analysis, phenotypic analysis, and clinical correlation.

Results  We identified clinically relevant genetic information in more than 60% of patients studied (n = 46), including diagnostic pathogenic gene variants in 21% (n = 16), a notable yield given the diverse genetics and clinical heterogeneity of the cerebellar ataxias.

Conclusions and Relevance  This study demonstrated that clinical exome sequencing in patients with adult-onset and sporadic presentations of ataxia is a high-yield test, providing a definitive diagnosis in more than one-fifth of patients and suggesting a potential diagnosis in more than one-third to guide additional phenotyping and diagnostic evaluation. Therefore, clinical exome sequencing is an appropriate consideration in the routine genetic evaluation of all patients presenting with chronic progressive cerebellar ataxia

JAMA Neurology 2014

Sleep is related to neuron numbers in the ventrolateral preoptic/intermediate nucleus in older adults with and without Alzheimer’s disease

Fragmented sleep is a common and troubling symptom in ageing and Alzheimer’s disease; however, its neurobiological basis in many patients is unknown. In rodents, lesions of the hypothalamic ventrolateral preoptic nucleus cause fragmented sleep. We previously proposed that the intermediate nucleus in the human hypothalamus, which has a similar location and neurotransmitter profile, is the homologue of the ventrolateral preoptic nucleus, but physiological data in humans were lacking. We hypothesized that if the intermediate nucleus is important for human sleep, then intermediate nucleus cell loss may contribute to fragmentation and loss of sleep in ageing and Alzheimer’s disease. We studied 45 older adults (mean age at death 89.2 years; 71% female; 12 with Alzheimer’s disease) from the Rush Memory and Aging Project, a community-based study of ageing and dementia, who had at least 1 week of wrist actigraphy proximate to death. Upon death a median of 15.5 months later, we used immunohistochemistry and stereology to quantify the number of galanin-immunoreactive intermediate nucleus neurons in each individual, and related this to ante-mortem sleep fragmentation. Individuals with Alzheimer’s disease had fewer galaninergic intermediate nucleus neurons than those without (estimate −2872, standard error = 829, P = 0.001). Individuals with more galanin-immunoreactive intermediate nucleus neurons had less fragmented sleep, after adjusting for age and sex, and this association was strongest in those for whom the lag between actigraphy and death was <1 year (estimate −0.0013, standard error = 0.0005, P = 0.023). This association did not differ between individuals with and without Alzheimer’s disease, and similar associations were not seen for two other cell populations near the intermediate nucleus. These data are consistent with the intermediate nucleus being the human homologue of the ventrolateral preoptic nucleus. Moreover, they demonstrate that a paucity of galanin-immunoreactive intermediate nucleus neurons is accompanied by sleep fragmentation in older adults with and without Alzheimer’s disease.

Brain 2014

Oxytocin improves behavioural and neural deficits in inferring others’ social emotions in autism

Recent studies have suggested oxytocin’s therapeutic effects on deficits in social communication and interaction in autism spectrum disorder through improvement of emotion recognition with direct emotional cues, such as facial expression and voice prosody. Although difficulty in understanding of others’ social emotions and beliefs under conditions without direct emotional cues also plays an important role in autism spectrum disorder, no study has examined the potential effect of oxytocin on this difficulty. Here, we sequentially conducted both a case-control study and a clinical trial to investigate the potential effects of oxytocin on this difficulty at behavioural and neural levels measured using functional magnetic resonance imaging during a psychological task. This task was modified from the Sally-Anne Task, a well-known first-order false belief task. The task was optimized for investigation of the abilities to infer another person’s social emotions and beliefs distinctively so as to test the hypothesis that oxytocin improves deficit in inferring others’ social emotions rather than beliefs, under conditions without direct emotional cues. In the case-control study, 17 males with autism spectrum disorder showed significant behavioural deficits in inferring others’ social emotions (P = 0.018) but not in inferring others’ beliefs (P = 0.064) compared with 17 typically developing demographically-matched male participants. They also showed significantly less activity in the right anterior insula and posterior superior temporal sulcus during inferring others’ social emotions, and in the dorsomedial prefrontal cortex during inferring others’ beliefs compared with the typically developing participants (P < 0.001 and cluster size > 10 voxels). Then, to investigate potential effects of oxytocin on these behavioural and neural deficits, we conducted a double-blind placebo-controlled crossover within-subject trial for single-dose intranasal administration of 24 IU oxytocin in an independent group of 20 males with autism spectrum disorder. Behaviourally, oxytocin significantly increased the correct rate in inferring others’ social emotions (P = 0.043, one-tail). At the neural level, the peptide significantly enhanced the originally-diminished brain activity in the right anterior insula during inferring others’ social emotions (P = 0.004), but not in the dorsomedial prefrontal cortex during inferring others’ beliefs (P = 0.858). The present findings suggest that oxytocin enhances the ability to understand others’ social emotions that have also required second-order false belief rather than first-order false beliefs under conditions without direct emotional cues in autism spectrum disorder at both the behaviour and neural levels.

Brain 2014

Discovering rare diseases: mutation in the Nuclear Encoded Mitochondrial Isoleucyl tRNA-Synthetase IARS2 in Patients with Cataracts, Growth Hormone Deficiency with Short Stature, Partial Sensorineural Deafness and Peripheral Neuropathy or with Leigh Syndrome.

Mutations in the nuclear-encoded mitochondrial aminoacyl-tRNA synthetases are associated with a range of clinical phenotypes. Here we report a novel disorder in three adult patients with a phenotype including cataracts, short stature secondary to growth hormone deficiency, sensorineural hearing deficit, peripheral sensory neuropathy and skeletal dysplasia. Using SNP genotyping and whole exome sequencing, we identified a single likely causal variant, a missense mutation in a conserved residue of the nuclear gene IARS2, encoding mitochondrial isoleucyl-tRNA synthetase. The mutation is homozygous in the affected patients, heterozygous in carriers, and absent in control chromosomes. IARS2 protein level was reduced in skin cells cultured from one of the patients, consistent with a pathogenic effect of the mutation. Compound heterozygous mutations in IARS2 were independently identified in a previously unreported patient with a more severe mitochondrial phenotype diagnosed as Leigh Syndrome. This is the first report of clinical findings associated with IARS2 mutations. This article is protected by copyright. All rights reserved.

Hum Mutat. 2014 Aug 

Copper supplementation restores cytochrome c oxidase assembly defect in a mitochondrial disease model of COA6 deficiency.

Mitochondrial respiratory chain biogenesis is orchestrated by hundreds of assembly factors, many of which are yet to be discovered. Using an integrative approach based on clues from evolutionary history, protein localization and human genetics, we have identified a conserved mitochondrial protein, C1orf31/COA6, and shown its requirement for respiratory complex IV biogenesis in yeast, zebrafish and human cells. A recent next-generation sequencing study reported potential pathogenic mutations within the evolutionarily conserved Cx₉CxnCx₁₀C motif of COA6, implicating it in mitochondrial disease biology. Using yeast coa6Δ cells, we show that conserved residues in the motif, including the residue mutated in a patient with mitochondrial disease, are essential for COA6 function, thus confirming the pathogenicity of the patient mutation. Furthermore, we show that zebrafish embryos with zfcoa6 knockdown display reduced heart rate and cardiac developmental defects, recapitulating the observed pathology in the human mitochondrial disease patient who died of neonatal hypertrophic cardiomyopathy. The specific requirement of Coa6 for respiratory complex IV biogenesis, its intramitochondrial localization and the presence of the Cx₉CxnCx₁₀C motif suggested a role in mitochondrial copper metabolism. In support of this, we show that exogenous copper supplementation completely rescues respiratory and complex IV assembly defects in yeast coa6Δ cells. Taken together, our results establish an evolutionarily conserved role of Coa6 in complex IV assembly and support a causal role of the COA6 mutation in the human mitochondrial disease patient.

Hum Mol Genet.2014

A Mutation of COX6A1 Causes a Recessive Axonal or Mixed Form of Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy characterized by clinical and genetic heterogeneity. Although more than 30 loci harboring CMT-causing mutations have been identified, many other genes still remain to be discovered for many affected individuals. For two consanguineous families with CMT (axonal and mixed phenotypes), a parametric linkage analysis using genome-wide SNP chip identified a 4.3 Mb region on 12q24 showing a maximum multipoint LOD score of 4.23. Subsequent whole-genome sequencing study in one of the probands, followed by mutation screening in the two families, revealed a disease-specific 5 bp deletion (c.247−10_247−6delCACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome coxidase subunit VIa polypeptide 1 (COX6A1), which is a component of mitochondrial respiratory complex IV (cytochrome c oxidase [COX]), within the autozygous linkage region. Functional analysis showed that expression of COX6A1 in peripheral white blood cells from the affected individuals and COX activity in their EB-virus-transformed lymphoblastoid cell lines were significantly reduced. In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking. Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT.

AJHG 2014

Directional steering. A novel approach to deep brain stimulation

Objective: The aim of this study was to investigate whether directional steering through a novel 32-contact electrode is safe and can modulate the thresholds for beneficial and side effects of stimulation.

Methods: The study is a single-center, performance and safety study. Double-blind intraoperative evaluations of the thresholds for therapeutic benefit and for side effects were performed in 8 patients with Parkinson disease while stimulating in randomized order in spherical mode and in 4 different steering modes with the 32-contact electrode, and in monopolar mode with a commercial electrode. In addition, simultaneous recordings of local field potentials through all 32 contacts were performed.

Results: There were no adverse events related to the experimental device. For 13 of 15 side effects (87%), the threshold could be increased by ≥1 mA while steering in at least one direction in comparison to conventional spherical stimulation, thereby increasing the therapeutic window by up to 1.5 mA. Recording local field potentials through all 32 electrode contacts yielded spatiotemporal information on pathologic neuronal activity.

Conclusions: Controlled steering of current through the brain may improve the effectiveness of deep brain stimulation (DBS), allow for novel applications, and provide a tool to better explore pathophysiologic activity in the brain.

Classification of evidence: This study provides Class IV evidence that for patients with Parkinson disease, steering DBS current is well tolerated, increases the threshold for side effects, and may improve the therapeutic window of subthalamic nucleus DBS as compared with current standard spherical stimulation.

Neurology 2014

Guidelines for uniform reporting of body fluid biomarker studies in neurologic disorders

Objective: The aim of these guidelines is to make the process of reporting body fluid biomarker studies in neurologic disorders more uniform and transparent, in line with existing standards for reporting research in other biomedical areas. Although biomarkers have been around for decades, there are concerns over the high attrition rate of promising candidate biomarkers at later phases of development.

Methods: BioMS-eu consortium, a collaborative network working toward improving the quality of biomarker research in neurologic disorders, discussed the merits of standardizing the reporting of body fluid biomarker research. A checklist of items integrating the results of other published guidances, literature, conferences, regulatory opinion, and personal expertise was created to ultimately form a structured summary guidance incorporating the key features.

Results: The summary guidance is comprised of a 10-point uniform reporting format ranging from introduction, materials and methods, through to results and discussion. Each item is discussed in detail in the guidance report.

Conclusions: To enhance the future development of body fluid biomarkers, it will be important to standardize the reporting of studies. This guideline by the BioMS-eu consortium is aimed at setting a standard for the reporting of future body fluid biomarker research studies in neurologic disorders. We anticipate that following these guidelines will help to accelerate the selection of biomarkers for clinical development.

Neurology 2014