Delayed-onset Friedreich's ataxia revisited

Background

Friedreich's ataxia usually occurs before the age of 25. Rare variants have been described, such as late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia, occurring after 25 and 40 years, respectively. We describe the clinical, functional, and molecular findings from a large series of late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia and compare them with typical-onset Friedreich's ataxia.

Methods

Phenotypic and genotypic comparison of 44 late-onset Friedreich's ataxia, 30 very late-onset Friedreich's ataxia, and 180 typical Friedreich's ataxia was undertaken.

Results

Delayed-onset Friedreich's ataxia (late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia) had less frequently dysarthria, abolished tendon reflexes, extensor plantar reflexes, weakness, amyotrophy, ganglionopathy, cerebellar atrophy, scoliosis, and cardiomyopathy than typical-onset Friedreich's ataxia, along with less severe functional disability and shorter GAA expansion on the smaller allele (P < 0.001). Delayed-onset Friedreich's ataxia had lower scale for the assessment and rating of ataxia and spinocerebellar degeneration functional scores and longer disease duration before wheelchair confinement (P < 0.001). Both GAA expansions were negatively correlated to age at disease onset (P < 0.001), but the smaller GAA expansion accounted for 62.9% of age at onset variation and the larger GAA expansion for 15.6%. In this comparative study of late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia, no differences between these phenotypes were demonstrated.

Conclusion

Typical- and delayed-onset Friedreich's ataxia are different and Friedreich's ataxia is heterogeneous. Late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia appear to belong to the same clinical and molecular continuum and should be considered together as “delayed-onset Friedreich's ataxia.” As the most frequently inherited ataxia, Friedreich's ataxia should be considered facing compatible pictures, including atypical phenotypes (spastic ataxia, retained reflexes, lack of dysarthria, and lack of extraneurological signs), delayed disease onset (even after 60 years of age), and/or slow disease progression.

Movement Disorders 2015

Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci

Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).

Neuron 2015

Body fluid biomarkers for multiple sclerosis—the long road to clinical application

There is a strong unmet clinical need for objective body fluid biomarkers to assist early diagnosis and estimate long-term prognosis, monitor treatment response and predict potential adverse effects in multiple sclerosis (MS). Here, we review recent studies (focusing on 2012 to early 2015) on body fluid markers in MS from the perspective of their clinical utility. Because the first step towards clinical implementation of a newly discovered biomarker is independent replication, we focus on biomarkers that have been validated in at least two independent cohorts. We also discuss recent data challenging earlier findings, and biomarkers for which new clinical uses are suggested. For early MS diagnosis and prediction of conversion from clinically isolated syndrome to MS, several new B-cell-associated candidate blood biomarkers have emerged. For prognosis, several novel axonal damage markers should be adopted to biomarker panels. The number of disease-modifying treatments for MS has increased sharply, but biomarkers for treatment response monitoring and adverse effect prediction are scarce, and markers for subtyping and staging of MS are still lacking. In view of the availability and implementation of several standardized protocols to optimize biomarker studies, we expect biomarker development for MS to be improved and accelerated, with clinical implementation in the near future.

Nature Reviews Neurology 2015

Monoamine neurotransmitter disorders—clinical advances and future perspectives

The monoamine neurotransmitter disorders are important genetic syndromes that cause disturbances in catecholamine (dopamine, noradrenaline and adrenaline) and serotonin homeostasis. These disorders result in aberrant monoamine synthesis, metabolism and transport. The clinical phenotypes are predominantly neurological, and symptoms resemble other childhood neurological disorders, such as dystonic or dyskinetic cerebral palsy, hypoxic ischaemic encephalopathy and movement disorders. As a consequence, monoamine neurotransmitter disorders are under-recognized and often misdiagnosed. The diagnosis of monoamine neurotransmitter disorders requires detailed clinical assessment, cerebrospinal fluid neurotransmitter analysis and further supportive diagnostic investigations. Prompt and accurate diagnosis of neurotransmitter disorders is paramount, as many are responsive to treatment. The treatment is usually mechanism-based, with the aim to reverse disturbances of monoamine synthesis and/or metabolism. Therapeutic intervention can lead to complete resolution of motor symptoms in some conditions, and considerably improve quality of life in others. In this Review, we discuss the clinical features, diagnosis and management of monoamine neurotransmitter disorders, and consider novel concepts, the latest advances in research and future prospects for therapy.

Nature Reviews Neurology 2015

Peripheral small fiber dysfunction and neuropathic pain in patients with Morvan syndrome

Morvan syndrome (MoS) is an autoimmune-mediated syndrome that is frequently associated with malignant thymoma and autoantibodies targeting contactin associated protein-like 2 (CASPR2-Abs). Neuropathic pain is a frequent clinical feature in MoS—encountered in 62% of patients—but the pain mechanisms are unknown. We studied 4 patients with MoS who had neuropathic pain and investigated whether this pain could be due to a selective involvement of small nerve fibers. Written consent was obtained from all patients, and the study was approved by the institutional review board of the University Claude Bernard Lyon 

Neeurology 2015

Extracellular matrix in the CNS Dynamic structure and clinical correlations

The extracellular matrix (ECM) occupies the space between neurons and glial cells and accounts for 10%–20% of the total volume of the brain. During CNS development, the ECM provides a microenvironment that regulates cell migration, axonal guidance, and synaptogenesis; in the adult CNS, it contributes to maintenance of synaptic stability and regulates repair following injury, in part by restricting aberrant remodeling. The ECM molecules may be arranged diffusely, forming an ECM matrix, or condense to create specific compartments in the extracellular space; these include perineuronal nets (PNNs), perisynaptic nets, and the basement membrane contributing to the blood–brain barrier (BBB).

Neurology 2015

Seizures as adverse events of antibiotic drugs A systematic review

Objective: Antibiotic drugs are commonly associated with seizures. Tailoring antibiotics to the individual risk for seizures is challenged as avoidance of certain antibiotic classes may no longer be possible due to the emergence of resistant bacteria. We performed a systematic review regarding the current evidence for seizures associated with all antibiotic classes, their underlying mechanisms, and predisposing factors.

Methods: The medical search engine PubMed was systematically screened to identify articles in English published between 1960 and 2013. All study designs were considered and evidence was assessed.

Results: We included 143 articles involving 25,712 patients and 25 different antibiotics. Evidence for antibiotic-related symptomatic seizures is low to very low, mainly deriving from studies regarding β-lactams, especially unsubstituted penicillins and fourth-generation cephalosporins, as well as carbapenems, mainly imipenem, all administered in high doses or in patients with renal dysfunction, brain lesions, or known epilepsy. Evidence regarding symptomatic seizures from fluoroquinolones only relies on case reports and case series with most reports for ciprofloxacin in patients with renal dysfunction, mental disorders, prior seizures, or coadministered theophylline.

Conclusions: Evidence for an association between antibiotic drugs and symptomatic seizures is low to very low (evidence Class III–IV). Despite this, numerous reports point to an increased risk for symptomatic seizures especially of unsubstituted penicillins, fourth-generation cephalosporins, imipenem, and ciprofloxacin in combination with renal dysfunction, brain lesions, and epilepsy. During administration of such antibiotics in patients with particular predispositions, close monitoring of serum levels is advocated. As most seizures associated with cephalosporins are nonconvulsive, continuous EEG should be considered in patients with altered levels of consciousness.

Neurology 2015

Temporal anteroinferior encephalocele An underrecognized etiology of temporal lobe epilepsy?

Objective: To report the increasing frequency with which temporal anteroinferior encephalocele is a cause of adult temporal lobe epilepsy, to illustrate the clinical and imaging characteristics of this condition, and to report its surgical treatment in a series of 23 adult patients.

Methods: Epilepsy patients diagnosed with temporal anteroinferior encephalocele from January 2006 to December 2013 in a national epilepsy reference center were included in this noninterventional study.

Results: Twenty-three epilepsy patients (14 female, mean age 43.8 years) were diagnosed with temporal anteroinferior encephalocele in our institute. Thirteen patients had ≥2 encephaloceles; 7 cases presented bilaterally. The estimated frequency of this condition was 0.3% among MRI examinations performed due to newly diagnosed epilepsy (n = 6) and 1.9% among drug-resistant patients referred to our center (n = 17). Nine patients with local encephalocele disconnection (n = 4) or anterior temporal lobectomy and amygdalohippocampectomy (n = 5) have become seizure-free (Engel 1) for a mean 2.8 years (range 3 months–6.2 years) of follow-up. Three patients with local encephalocele disconnection were almost seizure-free or exhibited worthwhile improvement. Histologically, all 12 surgical patients had gliosis at the base of the encephalocele; some had cortical laminar disorganization (n = 5) or mild hippocampal degeneration (n = 1).

Conclusions: The possibility of a temporal encephalocele should be considered when interpreting MRI examinations of patients with medically intractable focal epilepsy. These patients can significantly benefit from unitemporal epilepsy surgery, even in cases with bilateral encephaloceles.

Neurology 2015

Role for the microtubule-associated protein tau variant p.A152T in risk of α-synucleinopathies

Objective: To assess the importance of MAPT variant p.A152T in the risk of synucleinopathies.

Methods: In this case-control study, we screened a large global series of patients and controls, and assessed associations between p.A152T and disease risk. We included 3,229 patients with clinical Parkinson disease (PD), 442 with clinical dementia with Lewy bodies (DLB), 181 with multiple system atrophy (MSA), 832 with pathologically confirmed Lewy body disease (LBD), and 2,456 healthy controls.

Results: The minor allele frequencies (MAF) in clinical PD cases (0.28%) and in controls (0.2%) were not found to be significantly different (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.63–2.98, p = 0.42). However, a significant association was observed with clinical DLB (MAF 0.68%, OR 5.76, 95% CI 1.62–20.51, p = 0.007) and LBD (MAF 0.42%, OR 3.55, 95% CI 1.04–12.17, p = 0.04). Additionally, p.A152T was more common in patients with MSA compared to controls (MAF 0.55%, OR 4.68, 95% CI 0.85–25.72, p = 0.08) but this was not statistically significant and therefore should be interpreted with caution.

Conclusions: Overall, our findings suggest that MAPT p.A152T is a rare low penetrance variant likely associated with DLB that may be influenced by coexisting LBD and AD pathology. Given the rare nature of the variant, further studies with greater sample size are warranted and will help to fully explain the role of p.A152T in the pathogenesis of the synucleinopathies.

Neurology 2015

Immunoglobulin G4-related pathologic features in inflammatory neuropathies

Objective: To evaluate the pathologic significance of immunoglobulin G4 (IgG4) in patients with inflammatory peripheral neuropathy.

Methods: We clinicopathologically examined 149 consecutive patients with peripheral neuropathy who had clusters of inflammatory cells with or without vasculitis in sural nerve biopsy specimens and in whom we were able to assess the serum IgG4 levels.

Results: Elevation of serum IgG4 levels and infiltration of IgG4-positive plasma cells, which are currently defined as the diagnostic criteria for IgG4–related disease, were found in 35 and 29 patients, respectively. In the 44 patients exhibiting either elevated serum IgG4 levels or IgG4-positive cell infiltration, the diagnoses prior to the examination of IgG4 in serum and pathologic samples included microscopic polyangiitis (12 patients) and eosinophilic granulomatosis with polyangiitis, or Churg-Strauss syndrome (19 patients). Thirty-four patients (77%) had findings of vasculitis as indicated by the destruction or obstruction of the vessel walls. Sixteen (36%) of these patients had fibrinoid necrosis. Axonal degeneration without evidence of demyelination was observed irrespective of the presence of vasculitis. The extent of fibrosis, assessed as the fibrotic area in the epineurium, significantly correlated with the grade of IgG4-positive cell infiltration (p < 0.01).

Conclusions: Elevated serum IgG4 levels and infiltration of IgG4-positive plasma cells were observed in a subgroup of patients with inflammatory neuropathy, particularly in patients diagnosed with primary systemic vasculitis, including microscopic polyangiitis. Epineurial IgG4-positive plasma cell infiltration correlated with the extent of epineurial fibrosis.

Neurology 2015

Brain endothelial dysfunction in cerebral adrenoleukodystrophy

X-linked adrenoleukodystrophy is caused by mutations in the ABCD1 gene leading to accumulation of very long chain fatty acids. Its most severe neurological manifestation is cerebral adrenoleukodystrophy. Here we demonstrate that progressive inflammatory demyelination in cerebral adrenoleukodystrophy coincides with blood–brain barrier dysfunction, increased MMP9 expression, and changes in endothelial tight junction proteins as well as adhesion molecules. ABCD1, but not its closest homologue ABCD2, is highly expressed in human brain microvascular endothelial cells, far exceeding its expression in the systemic vasculature. Silencing of ABCD1 in human brain microvascular endothelial cells causes accumulation of very long chain fatty acids, but much later than the immediate upregulation of adhesion molecules and decrease in tight junction proteins. This results in greater adhesion and transmigration of monocytes across the endothelium. PCR-array screening of human brain microvascular endothelial cells after ABCD1 silencing revealed downregulation of both mRNA and protein levels of the transcription factor c-MYC (encoded by MYC). Interestingly, MYC silencing mimicked the effects of ABCD1 silencing on CLDN5 and ICAM1 without decreasing the levels of ABCD1 protein itself. Together, these data demonstrate that ABCD1 deficiency induces significant alterations in brain endothelium via c-MYC and may thereby contribute to the increased trafficking of leucocytes across the blood–brain barrier as seen in cerebral adrenouleukodystrophy.

Brain 2015

Body fluid biomarkers for multiple sclerosis—the long road to clinical application

There is a strong unmet clinical need for objective body fluid biomarkers to assist early diagnosis and estimate long-term prognosis, monitor treatment response and predict potential adverse effects in multiple sclerosis (MS). Here, we review recent studies (focusing on 2012 to early 2015) on body fluid markers in MS from the perspective of their clinical utility. Because the first step towards clinical implementation of a newly discovered biomarker is independent replication, we focus on biomarkers that have been validated in at least two independent cohorts. We also discuss recent data challenging earlier findings, and biomarkers for which new clinical uses are suggested. For early MS diagnosis and prediction of conversion from clinically isolated syndrome to MS, several new B-cell-associated candidate blood biomarkers have emerged. For prognosis, several novel axonal damage markers should be adopted to biomarker panels. The number of disease-modifying treatments for MS has increased sharply, but biomarkers for treatment response monitoring and adverse effect prediction are scarce, and markers for subtyping and staging of MS are still lacking. In view of the availability and implementation of several standardized protocols to optimize biomarker studies, we expect biomarker development for MS to be improved and accelerated, with clinical implementation in the near future.

Nature Reviews Neurology 2015

Monoamine neurotransmitter disorders—clinical advances and future perspectives

The monoamine neurotransmitter disorders are important genetic syndromes that cause disturbances in catecholamine (dopamine, noradrenaline and adrenaline) and serotonin homeostasis. These disorders result in aberrant monoamine synthesis, metabolism and transport. The clinical phenotypes are predominantly neurological, and symptoms resemble other childhood neurological disorders, such as dystonic or dyskinetic cerebral palsy, hypoxic ischaemic encephalopathy and movement disorders. As a consequence, monoamine neurotransmitter disorders are under-recognized and often misdiagnosed. The diagnosis of monoamine neurotransmitter disorders requires detailed clinical assessment, cerebrospinal fluid neurotransmitter analysis and further supportive diagnostic investigations. Prompt and accurate diagnosis of neurotransmitter disorders is paramount, as many are responsive to treatment. The treatment is usually mechanism-based, with the aim to reverse disturbances of monoamine synthesis and/or metabolism. Therapeutic intervention can lead to complete resolution of motor symptoms in some conditions, and considerably improve quality of life in others. In this Review, we discuss the clinical features, diagnosis and management of monoamine neurotransmitter disorders, and consider novel concepts, the latest advances in research and future prospects for therapy.

Nature Reviews Neurology 2015

Naturally Occurring Monoclonal Antibodies and Their Therapeutic Potential for Neurologic Diseases

Importance  Modulating the immune system does not reverse long-term disability in neurologic disorders. Better neuroregenerative and neuroprotective treatment strategies are needed for neuroinflammatory and neurodegenerative diseases.

Objective  To review the role of monoclonal, naturally occurring antibodies (NAbs) as novel therapeutic molecules for treatment of neurologic disorders.

Evidence Review  Peer-reviewed articles, including case reports, case series, retrospective reviews, prospective randomized clinical trials, and basic science reports, were identified in a PubMed search for articles about NAbs and neurologic disorders that were published from January 1, 1964, through June 30, 2015. We concentrated our review on multiple sclerosis, Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis.

Findings  Many insults, including trauma, ischemia, infection, inflammation, and neurodegeneration, result in irreversible damage to the central nervous system. Central nervous system injury often results in a pervasive inhibitory microenvironment that hinders regeneration. A common targeted drug development strategy is to identify molecules with high potency in animal models. Many approaches often fail in the clinical setting owing to a lack of efficacy in human diseases (eg, less than the response demonstrated in animal models) or a high incidence of toxic effects. An alternative approach is to identify NAbs in humans because these therapeutic molecules have potential physiologic function without toxic effects. NAbs of the IgG, IgA, or IgM isotype contain germline or close to germline sequences and are reactive to self-components, altered self-components, or foreign antigens. Our investigative group developed recombinant, autoreactive, natural human IgM antibodies directed against oligodendrocytes or neurons with therapeutic potential for central nervous system repair. One such molecule, recombinant HIgM22, directed against myelin and oligodendrocytes completed a successful phase 1 clinical trial without toxic effects with the goal of promoting remyelination in multiple sclerosis.

Conclusions and Relevance  Animal studies demonstrate that certain monoclonal NAbs are beneficial as therapeutic agents for neurologic diseases. This class of antibodies represents a unique source from which to develop a new class of disease-modifying therapies.

JAMA Neurology 2015

Association Between Atrial Fibrillation and Dementia in the General Population

Importance  Atrial fibrillation (AF) has been suggested as a risk factor for dementia since it may lead to chronic cerebral hypoperfusion and stroke. However, longitudinal studies assessing the association between AF and dementia have shown inconsistent results.

Objective  To determine the effect of AF on the risk of developing dementia during 20 years of follow-up.

Design, Setting, and Participants  The association of prevalent and incident AF with incident dementia was assessed from July 6, 1989, to February 4, 2010, in 6514 dementia-free participants in the prospective population-based Rotterdam Study. Data analysis was conducted from September 18, 2014, to April 17, 2015. Cox proportional hazards regression models adjusting for age, sex, and cardiovascular risk factors; censored for stroke; and stratified by median age were used. In addition, we investigated whether the association between incident AF and dementia varied according to the duration of exposure, categorized in 6-year time bands.

Exposures  Prevalent and incident AF.

Main Outcomes and Measures  Incident dementia, determined according to the Diagnostic and Statistical Manual of Mental Disorders (Third Edition Revised) and the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria.

Results  At baseline, 318 of 6514 participants (4.9%) had prevalent AF, and during 81 483 person-years of follow-up, 994 participants (15.3%) developed incident dementia. With findings presented as adjusted hazard ratio (95% CI), prevalent AF was related to an increased risk of dementia (1.33; 1.02-1.73). Among 6196 participants without prevalent AF during 79 003 person-years of follow-up, 723 participants (11.7%) developed incident AF and 932 individuals (15.0%) developed incident dementia. Incident AF was associated with an increased risk of dementia in younger participants (<67 years: 1.81; 1.11-2.94 vs ≥67 years: 1.12; 0.85-1.46; P = .02 for interaction). The risk of dementia was strongly associated with duration of exposure to AF in the younger participants (in the highest stratum: 3.30; 1.16-9.38; P = .003 for trend) but not in the elder participants (0.25; 0.04-1.86; P = .94 for trend).

Conclusions and Relevance  Atrial fibrillation is associated with an increased risk of dementia, independent of clinical stroke. This association was strongest for younger participants with the longest duration of AF. Future studies should investigate whether optimal treatment of AF can prevent or postpone dementia.

JAMA  Neurology 2015

Risk of Stroke at the Time of Carotid Occlusion

Importance  Many patients with asymptomatic carotid stenosis are offered carotid stenting for the prevention of carotid occlusion. However, this treatment may be inappropriate if the risk of stroke is low at the time of occlusion and with intensive medical therapy.

Objectives  To determine the risk resulting from progression to occlusion among patients with asymptomatic carotid stenosis and to assess the role of severity of carotid stenosis or the presence of contralateral occlusion as factors that may predict the risk of stroke or death after occlusion of a previously asymptomatic carotid stenosis.

Design, Setting, and Participants  We conducted a retrospective analysis of data collected from patients at the Stroke Prevention Clinic of Victoria Hospital from January 1, 1990 (when annual surveillance with carotid ultrasonography first began), through December 31, 1995, or the Stroke Prevention at University Hospital from January 1, 1995, through December 31, 2012. The last date of follow-up was August 26, 2014.

Exposures  A new carotid occlusion during annual monitoring with carotid duplex ultrasonography (index occlusion).

Main Outcomes and Measures  Ipsilateral stroke or transient ischemic attack, death from ipsilateral stroke, or death from unknown cause.

Results  Among 3681 patients in our clinic database with data on sequential annual carotid ultrasonographic examinations during the study period, 316 (8.6%) were asymptomatic before an index occlusion that occurred during observation. Most of the new occlusions (254 of 316 [80.4%]) occurred before 2002, when medical therapy was less intensive; the frequency decreased by quartile of years (P < .001, χ2test). Only 1 patient (0.3%) had a stroke at the time of the occlusion, and only 3 patients (0.9%) had an ipsilateral stroke during follow-up (all before 2005). In Kaplan-Meier survival analyses, neither severity of stenosis (P = .80, log-rank test) nor contralateral occlusion (P = .73) predicted the risk of ipsilateral stroke or transient ischemic attack, death from stroke, or death from unknown cause at a mean (SD) follow-up of 2.56 (3.64) years. In Cox proportional hazards regression analyses, only age (P = .02), sex (P = .01), and carotid plaque burden (P = .006) significantly predicted risk of those events.

Conclusions and Relevance  The risk of progression to carotid occlusion is well below the risk of carotid stenting or endarterectomy and has decreased markedly with more intensive medical therapy. Preventing carotid occlusion may not be a valid indication for stenting.

JAMA Neurology 2015

De novo FUS mutations are the most frequent genetic cause in early-onset German ALS patients.

In amyotrophic lateral sclerosis (ALS) patients with known genetic cause, mutations in chromosome 9 open reading frame 72 (C9orf72) and superoxide dismutase 1 (SOD1) account for most familial and late-onset sporadic cases, whereas mutations in fused in sarcoma (FUS) can be identified in just around 5% of familial and 1% of overall sporadic cases. There are only few reports on de novo FUS mutations in juvenile ALS patients. To date, no systematic evaluation on the frequency of de novo FUS mutations in early-onset ALS patients has been conducted. Here, we screened a cohort of 14 early-onset sporadic ALS patients (onset age <35 years) to determine the frequency of mutations in C9orf72, SOD1, and FUS in this defined patient cohort. All patients were recruited prospectively by a single center in a period of 38 months. No mutations were detected in SOD1 or C9orf72; however, we identified 6 individuals (43%) carrying a heterozygous FUS mutation including 1 mutation that has not been described earlier (c.1504delG [p.Asp502Thrfs*27]). Genetic testing of parents was possible in 5 families and revealed that the mutations in these patients arose de novo. Three of the 6 identified patients presented with initial bulbar symptoms. Our study identifies FUS mutations as the most frequent genetic cause in early-onset ALS. Genetic testing of FUS thus seems indicated in sporadic early-onset ALS patients especially if showing predominant bulbar symptoms and an aggressive disease course.

Neurobiol. Aging 2015

Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome

Abstract

SPOAN syndrome is a neurodegenerative disorder mainly characterized by spastic paraplegia, optic atrophy and neuropathy. Affected patients are wheelchair bound after 15 years old, with progressive joint contractures and spine deformities. SPOAN patients also have sub normal vision secondary to apparently non-progressive congenital optic atrophy. A potential causative gene was mapped at 11q13 ten years ago. Here we performed next-generation sequencing in SPOAN-derived samples. While whole-exome sequencing failed to identify the causative mutation, whole-genome sequencing allowed to detect a homozygous 216-bp deletion (chr11.hg19:g.66,024,557_66,024,773del) located at the non-coding upstream region of the KLC2 gene. Expression assays performed with patient's fibroblasts and motor neurons derived from SPOAN patients showed KLC2 overexpression. Luciferase assay in constructs with 216-bp deletion confirmed the overexpression of gene reporter, varying from 48 to 74%, as compared to wild-type. Knockdown and overexpression of klc2 in Danio rerio revealed mild to severe curly-tail phenotype, which is suggestive of a neuromuscular disorder. Overexpression of a gene caused by a small deletion in the non-coding region is a novel mechanism, which to the best of our knowledge, was never reported before in a recessive condition. Although the molecular mechanism of KLC2 up-regulation still remains to be uncovered, such example adds to the importance of non-coding regions in human pathology.

Hum Mol Genet 2015

Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study

Background

Spinocerebellar ataxias are dominantly inherited neurodegenerative diseases. As potential treatments for these diseases are being developed, precise knowledge of their natural history is needed. We aimed to study the long-term disease progression of the most common spinocerebellar ataxias: SCA1, SCA2, SCA3, and SCA6. Furthermore, we aimed to establish the order and occurrence of non-ataxia symptoms, and identify predictors of disease progression.

Methods

In this longitudinal cohort study (EUROSCA), we enrolled men and women with positive genetic testing for SCA1, SCA2, SCA3, or SCA6 and with progressive, otherwise unexplained ataxia who were aged 18 years or older from 17 ataxia referral centres in ten European countries. Patients were seen every year for 3 years, and at irregular intervals thereafter. The primary outcome was the scale for the assessment and rating of ataxia (SARA), and the inventory of non-ataxia signs (INAS). We used linear mixed models to analyse progression. To account for dropouts, we applied a pattern-mixture model. This study is registered with ClinicalTrials.gov, number NCT02440763.

Findings

Between July 1, 2005, and Aug 31, 2006, 526 patients with SCA1, SCA2, SCA3, or SCA6 were enrolled. We analysed data for 462 patients with at least one follow-up visit. Median observation time was 49 months (IQR 35–72). SARA progression data were best fitted with a linear model in all genotypes. Annual SARA score increase was 2·11 (SE 0·12) in patients with SCA1, 1·49 (0·07) in patients with SCA2, 1·56 (0·08) in patients with SCA3, and 0·80 (0·09) in patients with SCA6. The increase of the number of non-ataxia signs reached a plateau in SCA1, SCA2, and SCA3. In patients with SCA6, the number of non-ataxia symptoms increased linearly, but more slowly than in patients with SCA1, SCA2, and SCA3 (p<0·0001). Factors that were associated with faster progression of the SARA score were short duration of follow-up (p=0·0179), older age at inclusion (0.04 [SE 0·02] per additional year; p=0·0476), and longer repeat expansions (0·06 [SE 0·02] per additional repeat unit; p=0·0128) in SCA1, short duration of follow-up (p<0·0001), lower age at onset (–0·02 [SE 0·01] per additional year; p=0·0014), and lower baseline SARA score (–0·02 [SE 0·01] per additional SARA point; p=0·0083) in SCA2, and lower baseline SARA score (–0·03 [SE 0·01] per additional SARA point; p=0·0195) in SCA6. In SCA3, we did not identify factors that affected progression of the SARA score.

Interpretation

Our study provides quantitative data on the progression of the most common spinocerebellar ataxias based on a follow-up period that exceeds those of previous studies. Our data could prove useful for sample size calculation and patient stratification in interventional trials.

Lancet Neurology 2015

Eating behavior in frontotemporal dementia Peripheral hormones vs hypothalamic pathology

Objective: To contrast the relationships of hormonal eating peptides and hypothalamic volumes to eating behavior and metabolic changes (body mass index [BMI]) in behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA).

Methods: Seventy-five patients with dementia (19 bvFTD, 26 svPPA, and 30 Alzheimer disease dementia) and 23 controls underwent fasting blood analyses of leptin, ghrelin, cholecystokinin, peptide tyrosine tyrosine (PYY), and agouti-related peptide (AgRP) levels. On brain MRI anterior, posterior, and total hypothalamic volumes were measured. Relationships between endocrine measures, hypothalamic volumes, eating behaviors, and BMI were investigated.

Results: Levels of AgRP were higher in patients with bvFTD (69 ± 89 pg/mL) and svPPA (62 ± 81 pg/mL) compared with controls (23 ± 19 pg/mL, p < 0.01). No differences were found for leptin, oxytocin, cholecystokinin, ghrelin, and PYY levels. Patients with bvFTD and svPPA had higher scores on questionnaires measuring eating behaviors. Atrophy of the posterior and total hypothalamus was observed in the bvFTD group only. Linear regression modeling revealed that leptin and AgRP levels predicted BMI.

Conclusion: Eating abnormalities are multifactorial in FTD. In bvFTD, they are in part related to hypothalamic degeneration, with potential disintegration of the network connections between the hypothalamus and orbitofrontal cortex/reward pathways. In svPPA, although hypothalamic volumes are preserved, this group experiences elevated AgRP levels similar to bvFTD, which predicts BMI in both groups. This finding highlights the potential key role of AgRP in eating and metabolic changes and provides a potential target for treatment to modify disease progression.

Neurology 2015