Publications by authors named "Alexis Brice"

492 Publications

Alternative splicing of BUD13 determines the severity of a developmental disorder with lipodystrophy and progeroid features.

Genet Med 2022 Jun 6. Epub 2022 Jun 6.

Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France; Center of Clinical investigation 1431, National Institute of Health and Medical Research (INSERM), CHU, Besancon, France.

Purpose: In this study we aimed to identify the molecular genetic cause of a progressive multisystem disease with prominent lipodystrophy.

Methods: In total, 5 affected individuals were investigated using exome sequencing. Dermal fibroblasts were characterized using RNA sequencing, proteomics, immunoblotting, immunostaining, and electron microscopy. Subcellular localization and rescue studies were performed.

Results: We identified a lipodystrophy phenotype with a typical facial appearance, corneal clouding, achalasia, progressive hearing loss, and variable severity. Although 3 individuals showed stunted growth, intellectual disability, and died within the first decade of life (A1, A2, and A3), 2 are adults with normal intellectual development (A4 and A5). All individuals harbored an identical homozygous nonsense variant affecting the retention and splicing complex component BUD13. The nucleotide substitution caused alternative splicing of BUD13 leading to a stable truncated protein whose expression positively correlated with disease expression and life expectancy. In dermal fibroblasts, we found elevated intron retention, a global reduction of spliceosomal proteins, and nuclei with multiple invaginations, which were more pronounced in A1, A2, and A3. Overexpression of both BUD13 isoforms normalized the nuclear morphology.

Conclusion: Our results define a hitherto unknown syndrome and show that the alternative splice product converts a loss-of-function into a hypomorphic allele, thereby probably determining the severity of the disease and the survival of affected individuals.
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http://dx.doi.org/10.1016/j.gim.2022.05.004DOI Listing
June 2022

Genome-wide Association and Meta-analysis of Age-at-Onset in Parkinson Disease: Evidence From COURAGE-PD Consortium.

Neurology 2022 May 26. Epub 2022 May 26.

Sorbonne Université (SU) Unité Mixte de Recherche (UMR) 1127, INSERM U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.

Background And Objectives: Considerable heterogeneity exists in the literature concerning genetic determinants of the age of onset (AAO) of Parkinson's disease (PD), which could be attributed to lack of well-powered replication cohorts. The previous largest GWAS identified nd loci on chromosome (Chr) 4 with a significant influence on AAO of PD, these have not been independently replicated. The present study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.

Methods: A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) consortium. This was followed up by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson disease Genomics Consortium (IPDGC).

Results: The COURAGE-PD included a cohort of 8,535 patients with PD (91.9%: Europeans, 9.1%: East-Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD=11.6), with an under-representation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE=0.057). None of the loci reached genome-wide significance (P<5x10). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published variant as genetic determinant of AAO of PD with Bonferroni-corrected nominal levels of significance (P<0.025): (rs34311866:β(SE)=0.477(0.203), P=0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (N=25,950) led to the identification of two genome-wide significant association signals on Chr 4, including the previously reported locus (rs983361:β(SE)=0.720(0.122), P=3.13x10) and a novel locus (rs4698412:β(SE)=-0.526(0.096), P=4.41x10).

Discussion: Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.
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http://dx.doi.org/10.1212/WNL.0000000000200699DOI Listing
May 2022

Heterozygous PNPT1 Variants Cause Spinocerebellar Ataxia Type 25.

Ann Neurol 2022 Jul 7;92(1):122-137. Epub 2022 May 7.

Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, France.

Objective: Dominant spinocerebellar ataxias (SCA) are characterized by genetic heterogeneity. Some mapped and named loci remain without a causal gene identified. Here we applied next generation sequencing (NGS) to uncover the genetic etiology of the SCA25 locus.

Methods: Whole-exome and whole-genome sequencing were performed in families linked to SCA25, including the French family in which the SCA25 locus was originally mapped. Whole exome sequence data were interrogated in a cohort of 796 ataxia patients of unknown etiology.

Results: The SCA25 phenotype spans a slowly evolving sensory and cerebellar ataxia, in most cases attributed to ganglionopathy. A pathogenic variant causing exon skipping was identified in the gene encoding Polyribonucleotide Nucleotidyltransferase PNPase 1 (PNPT1) located in the SCA25 linkage interval. A second splice variant in PNPT1 was detected in a large Australian family with a dominant ataxia also mapping to SCA25. An additional nonsense variant was detected in an unrelated individual with ataxia. Both nonsense and splice heterozygous variants result in premature stop codons, all located in the S1-domain of PNPase. In addition, an elevated type I interferon response was observed in blood from all affected heterozygous carriers tested. PNPase notably prevents the abnormal accumulation of double-stranded mtRNAs in the mitochondria and leakage into the cytoplasm, associated with triggering a type I interferon response.

Interpretation: This study identifies PNPT1 as a new SCA gene, responsible for SCA25, and highlights biological links between alterations of mtRNA trafficking, interferonopathies and ataxia. ANN NEUROL 2022;92:122-137.
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http://dx.doi.org/10.1002/ana.26366DOI Listing
July 2022

Does the Expression and Epigenetics of Genes Involved in Monogenic Forms of Parkinson's Disease Influence Sporadic Forms?

Genes (Basel) 2022 03 8;13(3). Epub 2022 Mar 8.

Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, Sorbonne Université, 75013 Paris, France.

Parkinson's disease (PD) is a disorder characterized by a triad of motor symptoms (akinesia, rigidity, resting tremor) related to loss of dopaminergic neurons mainly in the . Diagnosis is often made after a substantial loss of neurons has already occurred, and while dopamine replacement therapies improve symptoms, they do not modify the course of the disease. Although some biological mechanisms involved in the disease have been identified, such as oxidative stress and accumulation of misfolded proteins, they do not explain entirely PD pathophysiology, and a need for a better understanding remains. Neurodegenerative diseases, including PD, appear to be the result of complex interactions between genetic and environmental factors. The latter can alter gene expression by causing epigenetic changes, such as DNA methylation, post-translational modification of histones and non-coding RNAs. Regulation of genes responsible for monogenic forms of PD may be involved in sporadic PD. This review will focus on the epigenetic mechanisms regulating their expression, since these are the genes for which we currently have the most information available. Despite technical challenges, epigenetic epidemiology offers new insights on revealing altered biological pathways and identifying predictive biomarkers for the onset and progression of PD.
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http://dx.doi.org/10.3390/genes13030479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8951612PMC
March 2022

De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia.

Mov Disord 2022 Jun 12;37(6):1175-1186. Epub 2022 Feb 12.

Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy.

Background: Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy.

Objectives: We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia.

Methods: We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants.

Results: We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat.

Conclusions: We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism. © 2022 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28959DOI Listing
June 2022

Safety and efficacy of riluzole in spinocerebellar ataxia type 2 in France (ATRIL): a multicentre, randomised, double-blind, placebo-controlled trial.

Lancet Neurol 2022 03 18;21(3):225-233. Epub 2022 Jan 18.

Department of Neurology, Sorbonne University, Paris Brain Institute (ICM Institut du Cerveau), INSERM, CNRS, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Paris, France; Department of Genetics, Neurogene National Reference Centre for Rare Diseases, Pitié-Salpêtrière University Hospital, Assistance Publique, Hôpitaux de Paris, Paris, France. Electronic address:

Background: Riluzole has been reported to be beneficial in patients with cerebellar ataxia; however, effectiveness in individual subtypes of disease is unclear due to heterogeneity in participants' causes and stages of disease. Our aim was to test riluzole in a single genetic disease, spinocerebellar ataxia type 2.

Methods: We did a randomised, double-blind, placebo-controlled, multicentre trial (the ATRIL study) at eight national reference centres for rare diseases in France that were part of the Neurogene National Reference Centre for Rare Diseases. Participants were patients with spinocerebellar ataxia type 2 with an age at disease onset of up to 50 years and a scale for the assessment and rating of ataxia (SARA) score of at least 5 and up to 26. Patients were randomly assigned centrally (1:1) to receive either riluzole 50 mg orally or placebo twice per day for 12 months. Two visits, at baseline and at 12 months, included clinical measures and 3T brain MRI. The primary endpoint was the proportion of patients whose SARA score improved by at least 1 point. Analyses were done in the intention-to-treat population (all participants who were randomly assigned) and were done with only the observed data (complete case analysis). This trial is registered at ClinicalTrials.gov (NCT03347344) and has been completed.

Findings: Between Jan 18, 2018, and June 14, 2019, we enrolled 45 patients. 22 patients were randomly assigned to receive riluzole and 23 to receive placebo. Median age was 42 years (IQR 36-57) in the riluzole group and 49 years (40-56) in the placebo group and 23 (51%) participants were women. All participants presented with moderate-stage disease, characterised by a median SARA score of 13·5 (IQR 9·5-16·5). The primary endpoint, SARA score improvement of at least 1 point after 12 months, was observed in seven patients (32%) in the treated group versus nine patients (39%) in the placebo group, with a mean difference of -10·3% (95% CI -37·4% to 19·2%; p=0·75). SARA score showed a median increase (ie, worsening) of 0·5 points (IQR -1·5 to 1·5) in the riluzole group versus 0·3 points (-1·0 to 2·5) in the placebo group (p=0·70). No serious adverse event was reported in the riluzole-treated group whereas four patients in placebo group had a serious adverse event (hepatic enzyme increase, fracture of external malleolus, rectorrhagia, and depression). The number of patients with adverse events was similar in both groups (riluzole 16 [73%] patients vs placebo 19 [83%] patients; p=0·49).

Interpretation: We were able to recruit 45 patients moderately affected by spinocerebellar ataxia type 2 for this trial. Riluzole did not improve clinical or radiological outcomes in these patients. However, our findings provide data on progression of spinocerebellar ataxia type 2 that might prove to be valuable for the design of other clinical trials.

Funding: French Ministry of Health.
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http://dx.doi.org/10.1016/S1474-4422(21)00457-9DOI Listing
March 2022

Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study.

Mov Disord 2022 04 8;37(4):857-864. Epub 2022 Jan 8.

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece.

Background: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding.

Objective: The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR).

Methods: We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry).

Results: Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12-2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37-4.56], P = 0.003; P-difference with women = 0.029).

Conclusions: Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28902DOI Listing
April 2022

Clinical and genetic spectra of 1550 index patients with hereditary spastic paraplegia.

Brain 2022 04;145(3):1029-1037

Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, 75013 Paris, France.

Hereditary spastic paraplegia refers to rare genetic neurodevelopmental and/or neurodegenerative disorders in which spasticity due to length-dependent damage to the upper motor neuron is a core sign. Their high clinical and genetic heterogeneity makes their diagnosis challenging. Multigene panels allow a high-throughput targeted analysis of the increasing number of genes involved using next-generation sequencing. We report here the clinical and genetic results of 1550 index cases tested for variants in a panel of hereditary spastic paraplegia related genes analysed in routine diagnosis. A causative variant was found in 475 patients (30.7%) in 35/65 screened genes. SPAST and SPG7 were the most frequently mutated genes, representing 142 (9.2%) and 75 (4.8%) index cases of the whole series, respectively. KIF1A, ATL1, SPG11, KIF5A and REEP1 represented more than 1% (>17 cases) each. There were 661 causative variants (382 different ones) and 30 of them were structural variants. This large cohort allowed us to obtain an overview of the clinical and genetic spectrum of hereditary spastic paraplegia in clinical practice. Because of the wide phenotypic variability, there was no very specific sign that could predict the causative gene, but there were some constellations of symptoms that were found often related to specific subtypes. Finally, we confirmed the diagnostic effectiveness of a targeted sequencing panel as a first-line genetic test in hereditary spastic paraplegia. This is a pertinent strategy because of the relative frequency of several known genes (i.e. SPAST, KIF1A) and it allows identification of variants in the rarest involved genes and detection of structural rearrangements via coverage analysis, which is less efficient in exome datasets. It is crucial because these structural variants represent a significant proportion of the pathogenic hereditary spastic paraplegia variants (∼6% of patients), notably for SPAST and REEP1. In a subset of 42 index cases negative for the targeted multigene panel, subsequent whole-exome sequencing allowed a theoretical diagnosis yield of ∼50% to be reached. We then propose a two-step strategy combining the use of a panel of genes followed by whole-exome sequencing in negative cases.
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http://dx.doi.org/10.1093/brain/awab386DOI Listing
April 2022

Motor neuron pathology in CANVAS due to RFC1 expansions.

Brain 2021 Dec 20. Epub 2021 Dec 20.

Sorbonne Université, Paris Brain Institute, APHP, INSERM, CNRS, Paris, France.

CANVAS caused by RFC1 biallelic expansions is a major cause of inherited sensory neuronopathy. Detection of RFC1 expansion is challenging and CANVAS can be associated with atypical features. We clinically and genetically characterized 50 patients, selected based on the presence of sensory neuronopathy confirmed by EMG. We screened RFC1 expansion by PCR, repeat-primed PCR, and Southern blotting of long-range PCR products, a newly developed method. Neuropathological characterization was performed on the brain and spinal cord of one patient. Most patients (88%) carried a biallelic (AAGGG)n expansion in RFC1. In addition to the core CANVAS phenotype (sensory neuronopathy, cerebellar syndrome, and vestibular impairment), we observed chronic cough (97%), oculomotor signs (85%), motor neuron involvement (55%), dysautonomia (50%), and parkinsonism (10%). Motor neuron involvement was found for 24 of 38 patients (63.1%). First motor neuron signs, such as brisk reflexes, extensor plantar responses, and/or spasticity, were present in 29% of patients, second motor neuron signs, such as fasciculations, wasting, weakness, or a neurogenic pattern on EMG in 18%, and both in 16%. Mixed motor and sensory neuronopathy was observed in 19% of patients. Among six non-RFC1 patients, one carried a heterozygous AAGGG expansion and a pathogenic variant in GRM1. Neuropathological examination of one RFC1 patient with an enriched phenotype, including parkinsonism, dysautonomia, and cognitive decline, showed posterior column and lumbar posterior root atrophy. Degeneration of the vestibulospinal and spinocerebellar tracts was mild. We observed marked astrocytic gliosis and axonal swelling of the synapse between first and second motor neurons in the anterior horn at the lumbar level. The cerebellum showed mild depletion of Purkinje cells, with empty baskets, torpedoes, and astrogliosis characterized by a disorganization of the Bergmann's radial glia. We found neuronal loss in the vagal nucleus. The pars compacta of the substantia nigra was depleted, with widespread Lewy bodies in the locus coeruleus, substantia nigra, hippocampus, entorhinal cortex, and amygdala. We propose new guidelines for the screening of RFC1 expansion, considering different expansion motifs. Here, we developed a new method to more easily detect pathogenic RFC1 expansions. We report frequent motor neuron involvement and different neuronopathy subtypes. Parkinsonism was more prevalent in this cohort than in the general population, 10% versus the expected 1% (p < 0.001). We describe, for the first time, the spinal cord pathology in CANVAS, showing the alteration of posterior columns and roots, astrocytic gliosis and axonal swelling, suggesting motor neuron synaptic dysfunction.
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http://dx.doi.org/10.1093/brain/awab449DOI Listing
December 2021

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.

Nat Genet 2021 12 6;53(12):1636-1648. Epub 2021 Dec 6.

Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
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http://dx.doi.org/10.1038/s41588-021-00973-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8648564PMC
December 2021

NPTX1 mutations trigger endoplasmic reticulum stress and cause autosomal dominant cerebellar ataxia.

Brain 2022 05;145(4):1519-1534

Sorbonne Université, Institut du Cerveau - Paris Brain Institute, ICM, INSERM U 1127, CNRS UMR 7225, APHP, Pitié-Salpêtrière University Hospital, 75013 Paris, France.

With more than 40 causative genes identified so far, autosomal dominant cerebellar ataxias exhibit a remarkable genetic heterogeneity. Yet, half the patients are lacking a molecular diagnosis. In a large family with nine sampled affected members, we performed exome sequencing combined with whole-genome linkage analysis. We identified a missense variant in NPTX1, NM_002522.3:c.1165G>A: p.G389R, segregating with the phenotype. Further investigations with whole-exome sequencing and an amplicon-based panel identified four additional unrelated families segregating the same variant, for whom a common founder effect could be excluded. A second missense variant, NM_002522.3:c.980A>G: p.E327G, was identified in a fifth familial case. The NPTX1-associated phenotype consists of a late-onset, slowly progressive, cerebellar ataxia, with downbeat nystagmus, cognitive impairment reminiscent of cerebellar cognitive affective syndrome, myoclonic tremor and mild cerebellar vermian atrophy on brain imaging. NPTX1 encodes the neuronal pentraxin 1, a secreted protein with various cellular and synaptic functions. Both variants affect conserved amino acid residues and are extremely rare or absent from public databases. In COS7 cells, overexpression of both neuronal pentraxin 1 variants altered endoplasmic reticulum morphology and induced ATF6-mediated endoplasmic reticulum stress, associated with cytotoxicity. In addition, the p.E327G variant abolished neuronal pentraxin 1 secretion, as well as its capacity to form a high molecular weight complex with the wild-type protein. Co-immunoprecipitation experiments coupled with mass spectrometry analysis demonstrated abnormal interactions of this variant with the cytoskeleton. In agreement with these observations, in silico modelling of the neuronal pentraxin 1 complex evidenced a destabilizing effect for the p.E327G substitution, located at the interface between monomers. On the contrary, the p.G389 residue, located at the protein surface, had no predictable effect on the complex stability. Our results establish NPTX1 as a new causative gene in autosomal dominant cerebellar ataxias. We suggest that variants in NPTX1 can lead to cerebellar ataxia due to endoplasmic reticulum stress, mediated by ATF6, and associated to a destabilization of NP1 polymers in a dominant-negative manner for one of the variants.
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http://dx.doi.org/10.1093/brain/awab407DOI Listing
May 2022

SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration.

Brain 2021 10;144(9):2798-2811

Hurvitz Brain Sciences Program, Sunnybrook Research Institute; Department of Medicine (Neurology), Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada.

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10-5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.
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http://dx.doi.org/10.1093/brain/awab171DOI Listing
October 2021

Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson's Disease.

J Parkinsons Dis 2022 ;12(1):267-282

Department of Neurology, Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Larissa, Greece.

Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation.

Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases.

Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017).

Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking.

Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.
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http://dx.doi.org/10.3233/JPD-212851DOI Listing
April 2022

Pathogenic Variants in Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia.

Front Neurol 2021 20;12:720201. Epub 2021 Aug 20.

Sorbonne Université, Institut du Cerveau-Paris Brain Institute, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France.

Hereditary spastic paraplegia is a clinically and genetically heterogeneous neurological entity that includes more than 80 disorders which share lower limb spasticity as a common feature. Abnormalities in multiple cellular processes are implicated in their pathogenesis, including lipid metabolism; but still 40% of the patients are undiagnosed. Our goal was to identify the disease-causing variants in Sudanese families excluded for known genetic causes and describe a novel clinico-genetic entity. We studied four patients from two unrelated consanguineous Sudanese families who manifested a neurological phenotype characterized by spasticity, psychomotor developmental delay and/or regression, and intellectual impairment. We applied next-generation sequencing, bioinformatics analysis, and Sanger sequencing to identify the genetic culprit. We then explored the consequences of the identified variants in patients-derived fibroblasts using targeted-lipidomics strategies. Two homozygous variants in segregated with the disease in the two studied families. encodes the main brain phosphatidylserine hydrolase. , we confirmed that loss of function reduces the levels of certain long-chain lysophosphatidylserine species while increases the levels of multiple phosphatidylserine species in patient's fibroblasts. loss of function is implicated in the pathogenesis of a novel form of complex hereditary spastic paraplegia.
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http://dx.doi.org/10.3389/fneur.2021.720201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417901PMC
August 2021

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.

JAMA Neurol 2021 10;78(10):1236-1248

Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.

Objective: To identify the genetic variants associated with juvenile ALS.

Design, Setting, And Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.

Main Outcomes And Measures: De novo variants present only in the index case and not in unaffected family members.

Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.

Conclusions And Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.
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http://dx.doi.org/10.1001/jamaneurol.2021.2598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406220PMC
October 2021

Plasma NfL levels and longitudinal change rates in and -associated diseases: from tailored references to clinical applications.

J Neurol Neurosurg Psychiatry 2021 12 4;92(12):1278-1288. Epub 2021 Aug 4.

Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France

Objective: Neurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in and cohorts from presymptomatic to clinical stages.

Methods: We analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of and patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical-genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index.

Results: pNfL levels increased with age in controls, from ~5 to~18 pg/mL (p<0.0001), progressing over time (mean annualised rate of change (ARC): +3.9%/year, p<0.0001). Patients displayed higher levels and greater longitudinal progression (ARC: +26.7%, p<0.0001), with gene-specific trajectories. patients had higher levels than (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades.

Conclusions: This study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression.

Trial Registration Numbers: NCT02590276 and NCT04014673.
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http://dx.doi.org/10.1136/jnnp-2021-326914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606463PMC
December 2021

Lack of evidence for association of UQCRC1 with autosomal dominant Parkinson's disease in Caucasian families.

Neurogenetics 2021 10 21;22(4):365-366. Epub 2021 Jul 21.

Sorbonne Université, INSERM, CNRS, Institut du Cerveau - Paris Brain Institute - ICM, 75013, Paris, France.

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http://dx.doi.org/10.1007/s10048-021-00647-4DOI Listing
October 2021

Monogenic PD in Brazil: a step towards precision medicine.

Arq Neuropsiquiatr 2021 07;79(7):563-564

Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, INSERM, CNRS, Département de Génétique, Hôpital Pitié-Salpêtrière, APHP, Paris, France.

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http://dx.doi.org/10.1590/0004-282X-ANP-2021-E007DOI Listing
July 2021

Propensity for somatic expansion increases over the course of life in Huntington disease.

Elife 2021 05 13;10. Epub 2021 May 13.

Sorbonne Université, Paris Brain Institute (ICM Institut du Cerveau), AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, Paris, France.

Recent work on Huntington disease (HD) suggests that somatic instability of CAG repeat tracts, which can expand into the hundreds in neurons, explains clinical outcomes better than the length of the inherited allele. Here, we measured somatic expansion in blood samples collected from the same 50 HD mutation carriers over a twenty-year period, along with post-mortem tissue from 15 adults and 7 fetal mutation carriers, to examine somatic expansions at different stages of life. Post-mortem brains, as previously reported, had the greatest expansions, but fetal cortex had virtually none. Somatic instability in blood increased with age, despite blood cells being short-lived compared to neurons, and was driven mostly by CAG repeat length, then by age at sampling and by interaction between these two variables. Expansion rates were higher in symptomatic subjects. These data lend support to a previously proposed computational model of somatic instability-driven disease.
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http://dx.doi.org/10.7554/eLife.64674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118653PMC
May 2021

Primary Progressive Aphasia Associated With Mutations: New Insights Into the Nonamyloid Logopenic Variant.

Neurology 2021 07 12;97(1):e88-e102. Epub 2021 May 12.

From Sorbonne Université (D.S., M.H., L.S., S.E., A.C., S.B., D.R., A.M., R.L., B.D., A.B., O.C., M.T., R.M., I.L.B.), Paris Brain Institute-Institut du Cerveau (ICM), Inserm U1127, CNRS UMR 7225, AP-HP-Hôpital Pitié-Salpêtrière; Reference Centre for Rare or Early Dementias (D.S., S.F., M.N.-L., M.H., A.F., L.S., S.E., D.R., A.M., R.L., B.D., M.T., R.M., I.L.B.), IM2A, Département de Neurologie, AP-HP-Hôpital Pitié-Salpêtrière; Aramis Project Team (D.S., S.E., S.B., A.M., O.C.), Inria Research Center of Paris; Centre of Excellence of Neurodegenerative Disease (CoEN) (M.H.), ICM, CIC Neurosciences, Département de Neurologie, AP-HP-Hôpital Pitié-Salpêtrière, Sorbonne Université; FrontLab (A.F., R.L., B.D., M.T., R.M., I.L.B.), Paris Brain Institute-Institut du Cerveau (ICM); Université Lille (V.D., F.P.), Inserm U1171, CHU Lille, DistAlz, LiCEND, CNR-MAJ; CMRR Service de Neurologie (P.C.), CHU de Limoges; Department of Neurology (J.P., A.G.), Toulouse University Hospital; ToNIC (J.P., A.G.), Toulouse NeuroImaging Centre, Inserm, UPS, University of Toulouse; Normandie Université (D.W., D.H.), UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Neurology and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine; Rouen University Hospital (O.M.), Department of Neurology; Normandie Université (O.M.), UNICAEN, PSL Research University, EPHE, INSERM, U1077, CHU de Caen Normandie, Neuropsychologie et Imagerie de la Mémoire Humaine, Caen; UF de Neurogénétique Moléculaire et Cellulaire (F.C.), Département de Génétique, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix; EPHE (A.C.), PSL Research University, Paris; CMRR Nouvelle Aquitaine/Institut des Maladies Neurodégénératives clinique (IMNc) (S.A.), CHU de Bordeaux Hôpital Pellegrin; Unit of Neurology of Memory and Language (M.S., J.L., C.R.-J.), GHU Paris Psychiatry and Neurosciences, University of Paris, Hôpital Sainte Anne; Université Paris-Saclay (M.S., J.L., C.R.-J.), CEA, CNRS, Inserm, BioMaps, Orsay; Aix Marseille Université (M.D.), INSERM, Institut de Neurosciences des Systèmes, Marseille; APHM (M.D.), Timone, Service de Neurologie et Neuropsychologie, APHM Hôpital Timone Adultes, Marseille; CHU Nantes (C.B.-B.), Inserm CIC04, Department of Neurology, Centre Mémoire de Ressources et Recherche, Nantes; Centre de génétique (C.T.-R.), Hôpital d'Enfants, CHU Dijon Bourgogne; CMRR Département de Neurologie (F.S.), Hôpitaux Civils, Colmar, INSERM U1118, Université de Strasbourg, Faculté de Médecine, 67085 Strasbourg; CMRR (A.G.), Département de Neurologie, CHU de Montpellier, Inserm U1061, Université de Montpellier i-site MUSE; Department of Neurology (F.E.-B.), CMRR Angers University Hospital, Angers, France; Department of Advanced Medical and Surgical Sciences (C.C.), University of Campania Luigi Vanvitelli, Naples, Italy; and Department of Neurology (M.L.G.-T.), Memory and Aging Center, University of California, San Francisco.

Objective: To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with (progranulin) mutations and to study their neuroanatomic correlates.

Methods: Patients with PPA carrying mutations (PPA-) were selected among a national prospective research cohort of 1,696 patients with frontotemporal dementia, including 235 patients with PPA. All patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and gray matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls and patients with sporadic PPA.

Results: Among the 235 patients with PPA, 45 (19%) carried mutations, and we studied 32 of these. We showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (n = 13, 41%), followed by nonfluent/agrammatic (nfvPPA; n = 9, 28%) and mixed forms (n = 8, 25%). Semantic variant was rather rare (n = 2, 6%). Patients with lvPPA, qualified as nonamyloid lvPPA, presented canonical logopenic deficit. Seven of 13 had a pure form; 6 showed subtle additional linguistic deficits not fitting criteria for mixed PPA and hence were labeled as logopenic-spectrum variant. GM atrophy involved primarily left posterior temporal gyrus, mirroring neuroanatomic changes of amyloid-positive-lvPPA. Patients with nfvPPA presented agrammatism (89%) rather than apraxia of speech (11%).

Conclusions: This study shows that the most frequent PPA variant associated with mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming gene-specific therapies.
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http://dx.doi.org/10.1212/WNL.0000000000012174DOI Listing
July 2021

Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson's disease.

Nat Genet 2021 06 6;53(6):787-793. Epub 2021 May 6.

Translational Genomics Core of Partners HealthCare Personalized Medicine, Cambridge, MA, USA.

A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10) and WWOX (HR = 2.12, P = 2.37 × 10) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.
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http://dx.doi.org/10.1038/s41588-021-00847-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459648PMC
June 2021

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.

Ann Neurol 2021 07 17;90(1):76-88. Epub 2021 May 17.

23andMe, Inc., Sunnyvale, CA.

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.

Methods: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers.

Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset.

Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.
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http://dx.doi.org/10.1002/ana.26094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252519PMC
July 2021

Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease.

Ann Neurol 2021 07 24;90(1):35-42. Epub 2021 May 24.

Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.

Objective: Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average ~ 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide association studies (GWAS) have identified numerous genetic risk factors for PD, however, it is unclear whether genetics contribute to disease etiology in a sex-specific manner.

Methods: In an effort to study sex-specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson's Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases.

Results: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (~ 20%).

Interpretation: We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients. ANN NEUROL 2021;90:41-48.
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http://dx.doi.org/10.1002/ana.26090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422907PMC
July 2021

Clinical Variability of -Associated Early-Onset Parkinsonism.

Front Neurol 2021 25;12:648457. Epub 2021 Mar 25.

Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, INSERM, CNRS, Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, CIC Neurosciences, Paris, France.

Autosomal recessive early-onset parkinsonism is clinically and genetically heterogeneous. Mutations of three genes, , and cause pure phenotypes usually characterized by levodopa-responsive Parkinson's disease. By contrast, mutations of other genes, including , and , cause rarer, more severe diseases with a poor response to levodopa, generally with additional atypical features. We performed data mining on a gene panel or whole-exome sequencing in 460 index cases with early-onset (≤ 40 years) Parkinson's disease, including 57 with autosomal recessive disease and 403 isolated cases. We identified two isolated cases carrying biallelic mutations of (double-heterozygous p.D791fs/p.Y232H and homozygous p. Y832C mutations) and two siblings with the recurrent homozygous p.R258Q mutation. All four variants were absent or rare in the Genome Aggregation Database, were predicted to be deleterious on analysis and were found to be highly conserved between species. The patient with both the previously unknown p.D791fs and p.Y232H mutations presented with dystonia-parkinsonism accompanied by a frontal syndrome and oculomotor disturbances at the age of 39. In addition, two siblings from an Algerian consanguineous family carried the homozygous p.R258Q mutation and presented generalized tonic-clonic seizures during childhood, with severe intellectual disability, followed by progressive parkinsonism during their teens. By contrast, the isolated patient with the homozygous p. Y832C mutation, diagnosed at the age of 20, had typical parkinsonism, with no atypical symptoms and slow disease progression. Our findings expand the mutational spectrum and phenotypic profile of -related parkinsonism.
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http://dx.doi.org/10.3389/fneur.2021.648457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027075PMC
March 2021

Plasma neurofilament light chain predicts cerebellar atrophy and clinical progression in spinocerebellar ataxia.

Neurobiol Dis 2021 06 23;153:105311. Epub 2021 Feb 23.

Sorbonne Université, ICM (Paris Brain Institute), AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, Paris, France; APHP Department of Genetics, Pitié-Salpêtrière University Hospital, Paris, France. Electronic address:

Neurofilament light chain (NfL) is a marker of brain atrophy and predictor of disease progression in rare diseases such as Huntington Disease, but also in more common neurological disorders such as Alzheimer's disease. The aim of this study was to measure NfL longitudinally in autosomal dominant spinocerebellar ataxias (SCAs) and establish correlation with clinical and imaging parameters. We enrolled 62 pathological expansions carriers (17 SCA1, 13 SCA2, 19 SCA3, and 13 SCA7) and 19 age-matched controls in a prospective biomarker study between 2011 and 2015 and followed for 24 months at the Paris Brain Institute. We performed neurological examination, brain 3 T MRI and plasma NfL measurements using an ultrasensitive single-molecule array at baseline and at the two-year follow-up visit. We evaluated NfL correlations with ages, CAG repeat sizes, clinical scores and volumetric brain MRIs. NfL levels were significantly higher in SCAs than controls at both time points (p < 0.001). Age-adjusted NfL levels were significantly correlated at baseline with clinical scores (p < 0.01). We identified optimal NfL cut-off concentrations to differentiate controls from carriers for each genotype (SCA1 16.87 pg/mL, SCA2, 19.1 pg/mL, SCA3 16.04 pg/mL, SCA7 16.67 pg/mL). For all SCAs, NfL concentration was stable over two years (p = 0.95) despite a clinical progression (p < 0.0001). Clinical progression between baseline and follow-up was associated with higher NfL concentrations at baseline (p = 0.04). Of note, all premanifest carriers with NfL levels close to cut off concentrations had signs of the disease at follow-up. For all SCAs, the higher the observed NfL, the lower the pons volume at baseline (p < 0.01) and follow-up (p = 0.02). Higher NfL levels at baseline in all SCAs predicted a decrease in cerebellar volume (p = 0.03). This result remained significant for SCA2 only among all genotypes (p = 0.02). Overall, plasma NfL levels at baseline in SCA expansion carriers predict cerebellar volume change and clinical score progression. NfL levels might help refine inclusion criteria for clinical trials in carriers with very subtle signs.
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http://dx.doi.org/10.1016/j.nbd.2021.105311DOI Listing
June 2021

Response to Park et al.

Genet Med 2021 06 24;23(6):1173-1174. Epub 2021 Feb 24.

Sorbonne Université, Institut du Cerveau-Paris Brain Institute (ICM), AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, Paris, France.

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http://dx.doi.org/10.1038/s41436-021-01105-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187143PMC
June 2021

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations.

Neurogenetics 2021 03 23;22(1):71-79. Epub 2021 Jan 23.

Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, DMU Neuroscience 6, Paris, France.

Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.
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http://dx.doi.org/10.1007/s10048-020-00633-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997841PMC
March 2021
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