Post-concussion symptoms and chronic pain after mild traumatic brain injury are modulated by multiple locus effect in the BDNF gene through the expression of antisense: A pilot prospective control study.

Background: Mild traumatic brain injury (mTBI) often results in post-concussion symptoms, chronic pain, and sleepiness. Genetic factors are thought to play an important role in poor prognosis. Aims: The aims of this study are to (1) document the prevalence of pain and post-concussion symptoms in mTBI patients in acute and chronic phases (2) determine whether candidate genes predispose to post-concussive symptoms and pain. Methods: Posttraumatic symptoms, evaluated using the Rivermead Post-Concussion Symptoms Questionnaire, and pain were assessed in 94 mTBI patients in the acute phase as well as in 22 healthy controls. Assessment was repeated in 36 patients after one year who agreed to participate in the follow-up visit. Gene polymorphisms and expression were assessed in mTBI patients and healthy controls. Results: In the acute phase, mTBI patients with pain (69%) presented more psychological symptoms and sleepiness and were less able to return to work than those without pain. At one year, 19% of mTBI patients had persistent pain and psychological distress. Two haplotypes (H2 and H3) in the brain-derived neurotrophic factor (BDNF) gene were shown to be respectively deleterious and protective against post-concussion symptoms and pain in both acute and chronic phases. Protective haplotype H3 was associated with a decreased expression of the anti-sense of BDNF (BDNF-AS). Deleterious haplotype H2 predicted the development of chronic pain at one year, whereas H3 was protective. Conclusions: This pilot study suggests a protective mechanism of a multilocus effect in BDNF, through BDNF-AS, against post-concussion symptoms and pain in the acute phase and possibly chronic pain at one year post-mTBI. The role of antisense RNA should be validated in larger cohorts.

Contexte: Le traumatisme cranio-cérébral léger (TCCL) donne souvent lieu à des symptômes post-commotionnels, de la douleur chronique et de la somnolence. On croit que des facteurs génétiques jouent un rôle important dans le pronostic défavorable.Buts: Les buts de cette étude sont : 1) documenter la prévalence de la douleur et des symptômes post-commotionnels chez les patients ayant subi un TCCL, au cours des phases aigue et chronique; ii) déterminer si des gènes du candidat le prédisposent à la douleur et aux symptômes post-commotionnels.Méthodes: La douleur et les symptômes post-traumatiques, évalués à l'aide du questionnaire Rivermead sur les symptômes post-commotionnels, ont été évalués chez 94 patients ayant subi un TCCL au cours de la phase aigue, ainsi que chez 22 sujets témoins. Après un an, 36 patients qui avaient accepté de participer à une visite de suivi ont à nouveau été évalués. Les polymorphismes et l'expression des gènes ont été évalués chez les patients ayant subi un TCCL et chez les sujets témoins.Résultats: Au cours de la phase aigue, les patients ayant subi un TCCL avec douleur (69 %) présentaient davantage de symptômes psychologiques et de somnolence et étaient moins aptes à retourner au travail que les patients sans douleur. Après un an, 19 % des patients ayant subi un TCCL souffraient d'une douleur persistante et de détresse psychologique. Deux haplotypes (H2 et H3) dans le gène BDNF se sont montrés respectivement délétère et protecteur contre les symptômes post-commotionnels et contre la douleur, tant au cours de la phase aigue que de la phase chronique. Le haplotype protecteur H3 a été associé à une diminution de l'expression de l'anti-sens de BDNF (BDNF-AS). Le haplotype délétère H2 a prédit le développement de la douleur chronique un an plus tard, tandis que H3 a été protecteur.Conclusions: Cette étude pilote suggère l'existence d'un mécanisme protecteur d'un effet multilocus dans BDNF à travers BDNF-AS, contre les symptômes post-commotionnels et la douleur au cours de la phase aigue et possiblement au cours de la phase chronique, un an après le TCCL. Le rôle de la RNA anti-sens devrait être validé avec de plus grandes cohortes.

Paternal Age Explains a Major Portion of De Novo Germline Mutation Rate Variability in Healthy Individuals.

De novo mutations (DNM) are an important source of rare variants and are increasingly being linked to the development of many diseases. Recently, the paternal age effect has been the focus of a number of studies that attempt to explain the observation that increasing paternal age increases the risk for a number of diseases. Using disease-free familial quartets we show that there is a strong positive correlation between paternal age and germline DNM in healthy subjects. We also observed that germline CNVs do not follow the same trend, suggesting a different mechanism. Finally, we observed that DNM were not evenly distributed across the genome, which adds support to the existence of DNM hotspots.

Novel SIL1 mutations cause cerebellar ataxia and atrophy in a French-Canadian family.

Two French-Canadian sibs with cerebellar ataxia and dysarthria were seen in our neurogenetics clinic. The older brother had global developmental delay and spastic paraplegia. Brain MRIs from these two affected individuals showed moderate to severe cerebellar atrophy. To identify the genetic basis for their disease, we conducted a whole exome sequencing (WES) investigation using genomic DNA prepared from the affected sibs and their healthy father. We identified two mutations in the SIL1 gene, which is reported to cause Marinesco-Sjögren syndrome. This study emphasizes how the diagnosis of patients with ataxic gait and cerebellar atrophy may benefit from WES to identify the genetic cause of their condition.

Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons. Causative mutations in the global RNA-processing proteins TDP-43 and FUS among others, as well as their aggregation in ALS patients, have identified defects in RNA metabolism as an important feature in this disease. Lethal congenital contracture syndrome 1 and lethal arthrogryposis with anterior horn cell disease are autosomal recessive fetal motor neuron diseases that are caused by mutations in another global RNA-processing protein, hGle1. In this study, we carried out the first screening of GLE1 in ALS patients (173 familial and 760 sporadic) and identified 2 deleterious mutations (1 splice site and 1 nonsense mutation) and 1 missense mutation. Functional analysis of the deleterious mutants revealed them to be unable to rescue motor neuron pathology in zebrafish morphants lacking Gle1. Furthermore, in HeLa cells, both mutations caused a depletion of hGle1 at the nuclear pore where it carries out an essential role in nuclear export of mRNA. These results suggest a haploinsufficiency mechanism and point to a causative role for GLE1 mutations in ALS patients. This further supports the involvement of global defects in RNA metabolism in ALS.

Dopamine transporter SLC6A3 genotype affects cortico-striatal activity of set-shifts in Parkinson's disease.

Parkinson's disease is a neurodegenerative condition that affects motor function along with a wide range of cognitive domains, including executive function. The hallmark of the pathology is its significant loss of nigrostriatal dopamine, which is necessary for the cortico-striatal interactions that underlie executive control. Striatal dopamine reuptake is mediated by the SLC6A3 gene (formerly named DAT1) and its polymorphisms, which have been largely overlooked in Parkinson's disease. Thirty patients (ages 53-68 years; 19 males, 11 females) at early stages of Parkinson's disease, were genotyped according to a 9-repeat (9R) or 10-repeat (10R) allele on the SLC6A3/DAT1 gene. They underwent neuropsychological assessment and functional magnetic resonance imaging while performing a set-shifting task (a computerized Wisconsin Card Sorting Task) that relies on fronto-striatal interactions. Patients homozygous on the 10R allele performed significantly better on working memory tasks than 9R-carrier patients. Most importantly, patients carrying a 9R allele exhibited less activation than their 10R homozygous counterparts in the prefrontal cortex, premotor cortex and caudate nucleus, when planning and executing a set-shift. This pattern was exacerbated for conditions that usually recruit the striatum compared to those that do not. This is the first study indicating that the SLC6A3/DAT1 genotype has a significant effect on fronto-striatal activation and performance in Parkinson's disease. This effect is stronger for conditions that engage the striatum. Longitudinal studies are warranted to assess this polymorphism's effect on the clinical evolution of patients with Parkinson's disease, especially with cognitive decline.

Therapies for ataxias.

OPINION STATEMENT: Ataxia can originate from many genetic defects, but also from nongenetic causes. To be able to provide treatment, the first step is to establish the right diagnosis. Once the cause of the ataxia is defined, some specific treatments may be available. For example, the nongenetic ataxias that arise from vitamin deficiencies can improve following treatment. In most cases, however, therapies do not cure the disease and are purely symptomatic. Physiotherapy and occupational therapy are effective in all type of ataxias and often remain the most efficient treatment option for these patients to maximize their quality of life.

Molecular aspects of hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by progressive lower limbs spasticity and weakness. What was first thought to be a small group of rare Mendelian disorder has now become a large group that includes many complex syndromes. While large families with defined modes of inheritance were used for the initial HSP gene discovery, new sequencing technologies have recently allowed the study of small families, with the identification of many new disease causative genes. These discoveries are slowly leading to a better understanding of the molecular mechanisms underlying HSP with the identification of precise disease pathways. These insights may lead to new therapeutic strategies for what is a group of largely untreatable diseases. This review looks at the key players involved in HSP and where they act in their specific pathways.

Expanding the clinical phenotype associated with ELOVL4 mutation: study of a large French-Canadian family with autosomal dominant spinocerebellar ataxia and erythrokeratodermia.

IMPORTANCE: The autosomal dominant spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative disorders with significant genetic heterogeneity. Despite the identification of 20 SCA genes, the cause of the disorder in a significant proportion of families with SCA remains unexplained. In 1972, a French-Canadian family segregating a combination of SCA and erythrokeratodermia variabilis (EKV) in an autosomal dominant fashion was described. OBJECTIVE: To map and identify the causative gene in this large family with SCA and EKV using a combination of linkage analysis and whole-exome sequencing. DESIGN, SETTING, AND PARTICIPANTS: A total of 32 individuals from the family have undergone complete neurologic and dermatologic examinations. MAIN OUTCOMES AND MEASURES: Mutations in ELOVL4 have been reported in families with macular degeneration. Recently, homozygous mutations were found in patients with ichthyosis, spastic paraplegia, and severe neurodevelopmental defects. In the present study, we report on a heterozygote mutation in ELOVL4 in affected individuals from the family with SCA and EKV. The mutation segregates with a milder phenotype consisting of early-onset patches of erythema and hyperkeratosis, as well as SCA manifesting in the fourth or fifth decade of life. RESULTS: We describe the mapping and the identification of a c.504G>C transversion in ELOVL4 resulting in the p.L168F substitution. We also provide clinical characterization of the phenotypes in 19 mutation carriers. CONCLUSIONS AND RELEVANCE: We report, to our knowledge, the first mutation in ELOVL4 that is associated with SCA and EKV. This gene encodes a member of the elongase family, which is responsible for the elongation of very long-chain fatty acids (at least 26 carbons). These fatty acids participate in a wide variety of physiological functions, including skin barrier formation and peroxisome ß-oxidation. Overall, these results provide additional insight into the pathogenesis of these complex neurodegenerative disorders.

Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia.

Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurological conditions. Their main pathogenic mechanisms are thought to involve alterations in endomembrane trafficking, mitochondrial function, and lipid metabolism. With a combination of whole-genome mapping and exome sequencing, we identified three mutations in REEP2 in two families with HSP: a missense variant (c.107T>A [p.Val36Glu]) that segregated in the heterozygous state in a family with autosomal-dominant inheritance and a missense change (c.215T>A [p.Phe72Tyr]) that segregated in trans with a splice site mutation (c.105+3G>T) in a family with autosomal-recessive transmission. REEP2 belongs to a family of proteins that shape the endoplasmic reticulum, an organelle that was altered in fibroblasts from an affected subject. In vitro, the p.Val36Glu variant in the autosomal-dominant family had a dominant-negative effect; it inhibited the normal binding of wild-type REEP2 to membranes. The missense substitution p.Phe72Tyr, in the recessive family, decreased the affinity of the mutant protein for membranes that, together with the splice site mutation, is expected to cause complete loss of REEP2 function. Our findings illustrate how dominant and recessive inheritance can be explained by the effects and nature of mutations in the same gene. They have also important implications for genetic diagnosis and counseling in clinical practice because of the association of various modes of inheritance to this new clinico-genetic entity.

Exome sequencing revealed PMM2 gene mutations in a French-Canadian family with congenital atrophy of the cerebellum.

Two affected and one unaffected siblings from a French-Canadian family were evaluated in our neurogenetic clinic. The oldest brother had intentional and postural hand tremor while his youngest sister presented mild ataxia, a similar hand tremor and global developmental delay. Brain MRIs of the two affected family members further revealed a significant cerebellar atrophy. For this study we conducted a whole exome sequencing (WES) investigation using genomic DNA prepared from the affected brother and sister, alongside DNA prepared from their unaffected mother, and identified two mutations previously reported to cause a rare disorder known as Congenital Disorder of Glycosylation, type Ia (CDG1A) (OMIM #212065). This study emphasizes how the diagnosis of patients presenting a mild tremor phenotype associated with cerebellar atrophy may benefit from WES in establishing genetic defects associated with their conditions.

SYNE1 mutations in autosomal recessive cerebellar ataxia.

IMPORTANCE: Autosomal recessive cerebellar ataxia type I, also known as recessive ataxia of Beauce, is a slowly progressive ataxia that leads to moderate disability with gait ataxia, dysarthria, dysmetria, mild oculomotor abnormalities, and diffuse cerebellar atrophy on brain imaging. Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene, located on chromosome 6p25, were first reported in patients who originated from a region known as "Beauce" in the province of Quebec, Canada. OBJECTIVE: To better evaluate the prevalence of SYNE1 mutations in individuals with mild pure cerebellar ataxia and cerebellar atrophy, we screened the gene in additional French-Canadian (FC) families and individuals from other populations. DESIGN, SETTING, AND PARTICIPANTS: Study participants were referred by their treating physician on the basis of core features of autosomal recessive cerebellar ataxia type I. After excluding individuals with known SYNE1 mutations, our cohort was composed mainly of 19 FCs and 21 individuals from other ethnic backgrounds. INTERVENTIONS: Extraction of DNA from blood samples and complete resequencing of the SYNE1 gene. MAIN OUTCOMES AND MEASURES: The involvement of SYNE1 mutations in individuals with ataxia worldwide by resequencing the SYNE1 gene. RESULTS: Two novel truncating mutations were found among the FC participants, and 2 other novel mutations were found in a patient from France and a patient from Brazil (1 mutation each). CONCLUSIONS AND RELEVANCE: This is the second report, to our knowledge, of SYNE1 gene mutations in a population other than FCs. These data suggest that mutations in SYNE1 should be investigated in families with cerebellar ataxia who live outside the FC region.

Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia.

Hereditary spastic paraplegias (HSPs) form a heterogeneous group of neurological disorders. A whole-genome linkage mapping effort was made with three HSP-affected families from Spain, Portugal, and Tunisia and it allowed us to reduce the SPG26 locus interval from 34 to 9 Mb. Subsequently, a targeted capture was made to sequence the entire exome of affected individuals from these three families, as well as from two additional autosomal-recessive HSP-affected families of German and Brazilian origins. Five homozygous truncating (n = 3) and missense (n = 2) mutations were identified in B4GALNT1. After this finding, we analyzed the entire coding region of this gene in 65 additional cases, and three mutations were identified in two subjects. All mutated cases presented an early-onset spastic paraplegia, with frequent intellectual disability, cerebellar ataxia, and peripheral neuropathy as well as cortical atrophy and white matter hyperintensities on brain imaging. B4GALNT1 encodes ß-1,4-N-acetyl-galactosaminyl transferase 1 (B4GALNT1), involved in ganglioside biosynthesis. These findings confirm the increasing interest of lipid metabolism in HSPs. Interestingly, although the catabolism of gangliosides is implicated in a variety of neurological diseases, SPG26 is only the second human disease involving defects of their biosynthesis.

Investigation of C9orf72 repeat expansions in Parkinson's disease.

Large repeat expansions in the C9orf72 gene were recently reported to be a major cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Given some of the clinical and pathologic overlap between these 2 diseases and Parkinson's disease, we sought to evaluate the presence of these expansions in a cohort of French-Canadian patients with Parkinson's disease. No pathologic expansion was found in our cohort of patients suggesting that C9orf72 repeat expansions do not play a major role in the pathogenesis of Parkinson's disease.

Exome sequencing identifies FUS mutations as a cause of essential tremor.

Essential tremor (ET) is a common neurodegenerative disorder that is characterized by a postural or motion tremor. Despite a strong genetic basis, a gene with rare pathogenic mutations that cause ET has not yet been reported. We used exome sequencing to implement a simple approach to control for misdiagnosis of ET, as well as phenocopies involving sporadic and senile ET cases. We studied a large ET-affected family and identified a FUS p.Gln290(∗) mutation as the cause of ET in this family. Further screening of 270 ET cases identified two additional rare missense FUS variants. Functional considerations suggest that the pathogenic effects of ET-specific FUS mutations are different from the effects observed when FUS is mutated in amyotrophic lateral sclerosis cases; we have shown that the ET FUS nonsense mutation is degraded by the nonsense-mediated-decay pathway, whereas amyotrophic lateral sclerosis FUS mutant transcripts are not.

Exome sequencing reveals SPG11 mutations causing juvenile ALS.

We report here the description of a nonconsanguineous family with 2 affected individuals with a recessively inherited juvenile motor neuron disease. Exome sequencing of these 2 affected individuals led us to identify 2 compound heterozygous deletions leading to a frameshift and a premature stop codon in the SPG11 gene. One of these deletions, c.5199delA in exon 30, has not been previously reported. Interestingly, these deletions are associated with an intrafamilial phenotypic heterogeneity as one affected has atypical juvenile amyotrophic lateral sclerosis (ALS) and the other has classical hereditary spastic paraplegia with thin corpus callosum. Our findings confirm SPG11 as a genetic cause of juvenile amyotrophic lateral sclerosis and indicate that SPG11 mutations could be associated with 2 different clinical phenotypes within the same family.

Early influence of the rs4675690 on the neural substrates of sadness.

BACKGROUND: CREB1 has previously been implicated in mood disorders, suicide, and antidepressant response. There is some evidence that the T allele in rs4675690, a single-nucleotide polymorphism near the CREB1 gene, is involved in the modulation of neural responses to negative stimuli. It is not known whether differential brain activity during negative mood state appears early in life in T allele carriers. METHODS: Functional magnetic resonance imaging (fMRI) was used to measure brain activity, during a transient state of sadness, in children homozygous for the T allele or the C allele. This primary emotion was selected given that it is the prevailing mood in major depressive disorder (MDD). Blood-oxygen-level dependent (BOLD) signal changes were measured while subjects viewed blocks of neutral film excerpts and blocks of sad film excerpts. RESULTS: There was significantly greater BOLD activation in the TT group, compared to the CC group, in the right dorsal anterior cingulate cortex (Brodmann area [BA 24]), right putamen, right caudate nucleus and left anterior temporal pole (BA 21), when the brain activity associated with the viewing of the emotionally neutral film excerpts was subtracted from that associated with the viewing of the sad film excerpts. LIMITATIONS: A replication study using larger samples may be required for more definitive conclusions. CONCLUSIONS: The different pattern of regional brain activation found here during transient sadness - in children carrying the T allele, compared to those carrying the C allele - might increase later in life susceptibility to emotional dysregulation and depressive symptoms.

Increased exonic de novo mutation rate in individuals with schizophrenia.

Schizophrenia is a severe psychiatric disorder that profoundly affects cognitive, behavioral and emotional processes. The wide spectrum of symptoms and clinical variability in schizophrenia suggest a complex genetic etiology, which is consistent with the numerous loci thus far identified by linkage, copy number variation and association studies. Although schizophrenia heritability may be as high as ∼80%, the genes responsible for much of this heritability remain to be identified. Here we sequenced the exomes of 14 schizophrenia probands and their parents. We identified 15 de novo mutations (DNMs) in eight probands, which is significantly more than expected considering the previously reported DNM rate. In addition, 4 of the 15 identified DNMs are nonsense mutations, which is more than what is expected by chance. Our study supports the notion that DNMs may account for some of the heritability reported for schizophrenia while providing a list of genes possibly involved in disease pathogenesis.