Collagen XXV alpha 1 (COL25A1) is a collagenous type II transmembrane protein purified from senile plaques of Alzheimer's disease (AD) brains. COL25A1 alleles have been associated with increased risk for AD in a Swedish population. COL25A1 is specifically expressed in neurons and binds to aggregated Abeta in vitro. However, its contribution to the pathogenesis of AD and in vivo function are unknown. Here, we report that over-expression of COL25A1 in transgenic mice increases p35/p25 and beta-site APP-cleaving enzyme 1 (BACE1) levels, facilitates intracellular aggregation and extracellular matrix deposits of Abeta, and causes synaptophysin loss and astrocyte activation. COL25A1 mice displayed reduced anxiety-like behavior in elevated plus maze and open field tests and significantly slower swimming speed in Morris water maze. In stable cell lines, motifs in noncollagenous domains of COL25A1 were important for the induction of BACE1 expression. These findings demonstrate that COL25A1 leads to AD-like pathology in vivo. Modulation of COL25A1 function may represent an alternative therapeutic intervention for AD.

Autosomal recessive hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) maps to the SPG11 locus in the majority of cases. Mutations in the KIAA1840 gene, encoding spatacsin, have been shown to underlie SPG11-linked HSP-TCC. The aim of this study was to perform candidate gene analysis in HSP-TCC subjects from Asian families and to characterize disruption of spatacsin function during zebrafish development. Homozygosity mapping and direct sequencing were used to assess the ACCPN, SPG11, and SPG21 loci in four inbred kindreds originating from the Indian subcontinent. Four novel homozygous SPG11 mutations (c.442+1G>A, c.2146C>T, c.3602_3603delAT, and c.4846C>T) were identified, predicting a loss of spatacsin function in each case. To investigate the role of spatacsin during development, we additionally ascertained the complete zebrafish spg11 ortholog by reverse transcriptase PCR and 5′ RACE. Analysis of transcript expression through whole-mount in situ hybridization demonstrated ubiquitous distribution, with highest levels detected in the brain. Morpholino antisense oligonucleotide injection was used to knock down spatacsin function in zebrafish embryos. Examination of spg11 morphant embryos revealed a range of developmental defects and CNS abnormalities, and analysis of axon pathway formation demonstrated an overall perturbation of neuronal differentiation. These data confirm loss of spatacsin as the cause of SPG11-linked HSP-TCC in Asian kindreds, expanding the mutation spectrum recognized in this disorder. This study represents the first investigation in zebrafish addressing the function of a causative gene in autosomal recessive HSP and identifies a critical role for spatacsin during early neural development in vivo.

Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders, caused or modified by an unstable CAG-repeat expansion in the SCA2 gene, which encodes a polyglutamine (polyQ) domain expansion in ataxin-2 (ATXN2). ATXN2 is an RNA-binding protein and interacts with the poly(A)-binding protein PABPC1, localizing to ribosomes at the rough endoplasmic reticulum. Under cell stress, ATXN2, PABPC1 and small ribosomal subunits are relocated to stress granules, where mRNAs are protected from translation and from degradation. It is unknown whether ATXN2 associates preferentially with specific mRNAs or how it modulates RNA processing. Here, we investigated the RNA profile of the liver and cerebellum from Atxn2 knockout (Atxn2 (-/-)) mice at two adult ages, employing oligonucleotide microarrays. Prominent increases were observed for Lsm12/Paip1 (>2-fold), translation modulators known as protein interactor/competitor of ATXN2 and for Plin3/Mttp (>1.3-fold), known as apolipoprotein modulators in agreement with the hepatosteatosis phenotype of the Atxn2 (-/-) mice. Consistent modest upregulations were also observed for many factors in the ribosome and the translation/secretion apparatus. Quantitative reverse transcriptase PCR in liver tissue validated >1.2-fold upregulations for the ribosomal biogenesis modulator Nop10, the ribosomal components Rps10, Rps18, Rpl14, Rpl18, Gnb2l1, the translation initiation factors Eif2s2, Eif3s6, Eif4b, Pabpc1 and the rER translocase factors Srp14, Ssr1, Sec61b. Quantitative immunoblots substantiated the increased abundance of NOP10, RPS3, RPS6, RPS10, RPS18, GNB2L1 in SDS protein fractions, and of PABPC1. In mouse embryonal fibroblasts, ATXN2 absence also enhanced phosphorylation of the ribosomal protein S6 during growth stimulation, while impairing the rate of overall protein synthesis rates, suggesting a block between the enhanced translation drive and the impaired execution. Thus, the physiological role of ATXN2 subtly modifies the abundance of cellular translation factors as well as global translation.

Tau is a major microtubule-associated protein in brain neurons. Its misfolding and accumulation cause neurodegenerative diseases characterized by brain atrophy and dementia, named tauopathies. Genetic forms are caused by mutations of microtubule-associated protein tau gene (MAPT). Tau is expressed also in nonneural tissues such as lymphocytes. Tau has been recently recognized as a multifunctional protein, and in particular, some findings supported a role in genome stability. In fact, peripheral cells of patients affected by frontotemporal dementia carrying different MAPT mutations showed structural and numerical chromosome aberrations. The aim of this study was to assess chromosome stability in peripheral cell from two animal models of genetic tauopathy, JNPL3 and PS19 mouse strains expressing the human tau carrying the P301L and P301S mutations, respectively, to confirm the previous data on humans. After demonstrating the presence of mutated tau in spleen, we performed standard cytogenetic analysis of splenic lymphocytes from homozygous and hemizygous JNPL3, hemizygous PS19, and relevant controls. Losses and gains of chromosomes (aneuploidy) were evaluated. We detected a significantly higher level of aneuploidy in JNPL3 and PS19 than in control mice. Moreover, in JNPL3, the aneuploidy was higher in homozygotes than in hemizygotes, demonstrating a gene dose effect, which appeared also to be age independent. Our results show that mutated tau is associated with chromosome instability. It is conceivable to hypothesize that in genetic tauopathies the aneuploidy may be present also in central nervous system, possibly contributing to neurodegeneration.

Axenfeld-Rieger syndrome (ARS) is a disorder affecting the anterior segment of the eye, often leading to secondary glaucoma and several systemic malformations. It is inherited in an autosomal dominant fashion that has been associated with genetic defects in PITX2 and FOXC1. Known genes CYP1b1, PITX2, and FOXC1 were excluded by Sanger sequencing. The purpose of current study is to identify the underlying genetic causes in ARS family by whole exome sequencing (WES). WES was performed for affected proband of family, and variants were prioritized based on in silico analyses. Segregation analysis of candidate variants was performed in family members. A novel heterozygous PRDM5 missense variant (c.877A>G; p.Lys293Glu) was found to segregate with the disease in an autosomal dominant fashion. The novel missense variant was absent from population-matched controls, the Exome Variant Server, and an in-house exome variant database. The Lys293Glu variant is predicted to be pathogenic and affects a lysine residue that is conserved in different species. Variants in the PRDM5 gene were previously identified in anterior segment defects, i.e., autosomal recessive brittle cornea syndrome and keratoconus. The results of this study suggest that genetic variants in PRDM5 can lead to various syndromic and nonsyndromic disorders affecting the anterior segment of the eye.

Autism is a neurodevelopmental disorder of complex genetics, characterized by impairment in social interaction and communication, as well as repetitive behavior. Multiple lines of evidence, including alterations in levels of GABA and GABA receptors in autistic patients, indicate that the GABAergic system, which is responsible for synaptic inhibition in the adult brain, may be involved in autism. Previous studies in our lab indicated association of noncoding single nucleotide polymorphisms (SNPs) within a GABA receptor subunit gene on chromosome 4, GABRA4, and interaction between SNPs in GABRA4 and GABRB1 (also on chromosome 4), within Caucasian autism patients. Studies of genetic variation in African-American autism families are rare. Analysis of 557 Caucasian and an independent population of 54 African-American families with 35 SNPs within GABRB1 and GABRA4 strengthened the evidence for involvement of GABRA4 in autism risk in Caucasians (rs17599165, p=0.0015; rs1912960, p=0.0073; and rs17599416, p=0.0040) and gave evidence of significant association in African-Americans (rs2280073, p=0.0287 and rs16859788, p=0.0253). The GABRA4 and GABRB1 interaction was also confirmed in the Caucasian dataset (most significant pair, rs1912960 and rs2351299; p=0.004). Analysis of the subset of families with a positive history of seizure activity in at least one autism patient revealed no association to GABRA4; however, three SNPs within GABRB1 showed significant allelic association; rs2351299 (p=0.0163), rs4482737 (p=0.0339), and rs3832300 (p=0.0253). These results confirmed our earlier findings, indicating GABRA4 and GABRB1 as genes contributing to autism susceptibility, extending the effect to multiple ethnic groups and suggesting seizures as a stratifying phenotype.

We have previously established a first whole genome transcriptomic profile of sporadic Parkinson's disease (PD). After extensive brain tissue-based validation combined with cycles of iterative data analysis and by focusing on the most comparable cases of the cohort, we have refined our analysis and established a list of 892 highly dysregulated priority genes that are considered to form the core of the diseased Parkinsonian metabolic network. The substantia nigra pathways, now under scrutiny, contain more than 100 genes whose association with PD is known from the literature. Of those, more than 40 genes belong to the highly significantly dysregulated group identified in our dataset. Apart from the complete list of 892 priority genes, we present pathways revealing PD 'hub' as well as 'peripheral' network genes. The latter include Lewy body components or interact with known PD genes. Biological associations of PD with cancer, diabetes and inflammation are discussed and interactions of the priority genes with several drugs are provided. Our study illustrates the value of rigorous clinico-pathological correlation when analysing high-throughput data to make optimal use of the histopathological phenome, or morphonome which currently serves as the key diagnostic reference for most human diseases. The need for systematic human tissue banking, following the highest possible professional and ethical standard to enable sustainability, becomes evident.

Genome wide association studies (GWAS) for Parkinson's disease (PD) have previously revealed a significant association with a locus on chromosome 7p15.3, initially designated as the glycoprotein non-metastatic melanoma protein B (GPNMB) locus. In this study, the functional consequences of this association on expression were explored in depth by integrating different expression quantitative trait locus (eQTL) datasets (Braineac, CAGEseq, GTEx, and Phenotype-Genotype Integrator (PheGenI)). Top risk SNP rs199347 eQTLs demonstrated increased expressions of GPNMB, KLHL7, and NUPL2 with the major allele (AA) in brain, with most significant eQTLs in cortical regions, followed by putamen. In addition, decreased expression of the antisense RNA KLHL7-AS1 was observed in GTEx. Furthermore, rs199347 is an eQTL with long non-coding RNA (AC005082.12) in human tissues other than brain. Interestingly, transcript-specific eQTLs in immune-related tissues (spleen and lymphoblastoid cells) for NUPL2 and KLHL7-AS1 were observed, which suggests a complex functional role of this eQTL in specific tissues, cell types at specific time points. Significantly increased expression of GPNMB linked to rs199347 was consistent across all datasets, and taken in combination with the risk SNP being located within the GPNMB gene, these results suggest that increased expression of GPNMB is the causative link explaining the association of this locus with PD. However, other transcript eQTLs and subsequent functional roles cannot be excluded. This highlights the importance of further investigations to understand the functional interactions between the coding genes, antisense, and non-coding RNA species considering the tissue and cell-type specificity to understand the underlying biological mechanisms in PD.

Chronic postsurgical pain (CPSP) is a debilitating chronic pain condition that has a substantial effect on quality of life. CPSP shows considerable clinical overlap with different chronic peripheral pain syndromes, suggesting a shared aetiology. This study aims to assess the genetic overlap between different chronic pain syndromes and CPSP, providing relevant biological context for potential chronic pain markers of CPSP. To analyse the genetic overlap between CPSP and chronic peripheral pain syndromes, recent GWAS studies were combined for polygenic risk scores (PRS) analysis, using a cohort of CPSP patients as starting point. Biological contextualisation of genetic marker, overlap between CPSP and chronic pain syndromes, was assessed through Gene Ontology (GO), using Pathway Scoring Algorithm (PASCAL) and REVIGO. PRS analyses suggest a significant genetic overlap between CPSP and 3 chronic pain disorders: chronic widespread pain (CWP, p value threshold = 0.003, R2 0.06, p = 0.003), rheumatoid arthritis (RA, p value threshold = 0.0177, R2 = 0.04, p = 0.017) and possibly sciatica (p value threshold = 0.00025, R2 = 0.03, p = 0.045). Whereas no significant genetic overlap was found with cluster headache and migraine, the outcome for osteoarthritis (OA) was inconsistent between the cohorts. This is likely related to cohort composition, as repeated random reallocation of patients' nullified CPSP/OA outcome variation between the discovery and replication cohorts. GO analyses suggested an aetiological involvement of genetic markers that control neurological signalling (specifically sodium channels) and inflammatory response. The current study reaffirms the impact of sample size, cohort composition and open data accessibility on the unbiased identification of genetic overlap across disorders. In conclusion, this study is the first to report genetic overlap between regulatory processes implicated in CPSP and chronic peripheral pain syndromes. Interaction between neurological signalling and inflammatory response may explain the genetic overlap between CPSP, CWP and RA. Enhanced understanding of mechanisms underlying chronification of pain will aid the development of new therapeutic strategies for CPSP with sodium channel biochemistry as a potential candidate.

The most recent genome-wide association study of migraine increased the total number of known migraine risk loci to 38. Still, most of the heritability of migraine remains unexplained, and it has been suggested that rare gene dysregulatory variants play an important role in migraine etiology. Addressing the missing heritability of migraine, we aim to fine-map signals from the known migraine risk loci to regulatory mechanisms and associate these to downstream genic targets. We analyzed a large cohort of whole-genome sequenced patients from extended migraine pedigrees (1040 individuals from 155 families). We test for association between rare variants segregating in regulatory regions with migraine. The findings were replicated in an independent case-control cohort (2027 migraineurs, 1650 controls). We report an increased burden of rare variants in one CpG island and three polycomb group response elements near four migraine risk loci. We found that the association is independent of the common risk variants in the loci. The regulatory regions are suggested to affect different genes than those originally tagged by the index SNPs of the migraine loci. Families with familial clustering of migraine have an increased burden of rare variants in regulatory regions near known migraine risk loci, with effects that are independent of the variants in the loci. The possible regulatory targets suggest different genes than those originally tagged by the index SNPs of the migraine loci.

Mitochondrial dysfunction may activate innate immunity, e.g. upon abnormal handling of mitochondrial DNA in TFAM mutants or in altered mitophagy. Recent reports showed that also deletion of mitochondrial matrix peptidase ClpP in mice triggers transcriptional upregulation of inflammatory factors. Here, we studied ClpP-null mouse brain at two ages and mouse embryonal fibroblasts, to identify which signaling pathways are responsible, employing mass spectrometry, subcellular fractionation, immunoblots, and reverse transcriptase polymerase chain reaction. Several mitochondrial unfolded protein response factors showed accumulation and altered migration in blue-native gels, prominently the co-chaperone DNAJA3. Its mitochondrial dysregulation increased also its extra-mitochondrial abundance in the nucleus, a relevant observation given that DNAJA3 modulates innate immunity. Similar observations were made for STAT1, a putative DNAJA3 interactor. Elevated expression was observed not only for the transcription factors Stat1/2, but also for two interferon-stimulated genes (Ifi44, Gbp3). Inflammatory responses were strongest for the RLR pattern recognition receptors (Ddx58, Ifih1, Oasl2, Trim25) and several cytosolic nucleic acid sensors (Ifit1, Ifit3, Oas1b, Ifi204, Mnda). The consistent dysregulation of these factors from an early age might influence also human Perrault syndrome, where ClpP loss-of-function leads to early infertility and deafness, with subsequent widespread neurodegeneration.

The term SCA refers to a phenotypically and genetically heterogeneous group of autosomal dominant spinocerebellar ataxias. Phenotypically they present as gait ataxia frequently in combination with dysarthria and oculomotor problems. Additional signs and symptoms are common and can include various pyramidal and extrapyramidal signs and intellectual impairment. Genetic causes of SCAs are either repeat expansions within disease genes or common mutations (point mutations, deletions, insertions etc.). Frequently the two types of mutations cause indistinguishable phenotypes (locus heterogeneity). This article focuses on SCAs caused by common mutations. It describes phenotype and genotype of the presently 27 types known and discusses the molecular pathogenesis in those 21 types where the disease gene has been identified. Apart from the dominant types, the article also summarizes findings in a variant caused by mutations in a mitochondrial gene. Possible common disease mechanisms are considered based on findings in the various SCAs described.

Mutations in the SLC20A2-gene encoding the inorganic phosphate (Pi) transporter PiT2 can explain approximately 40% of the familial cases of the rare neurodegenerative disorder primary familial brain calcification (Fahr's disease). The disease characteristic, cerebrovascular-associated calcifications, is also present in Slc20a2-knockout (KO) mice. Little is known about the specific role(s) of PiT2 in the brain. Recent in vitro studies, however, suggest a role in regulation of the [Pi] in cerebrospinal fluid (CSF). We here show that Slc20a2-KO mice indeed have a high CSF [Pi] in agreement with a role of PiT2 in Pi export from the CSF. The implications in relation to disease mechanism are discussed.

Bovine spinal dysmyelination (BSD) is a recessive congenital neurodegenerative disease in cattle (Bos taurus) characterized by pathological changes of the myelin sheaths in the spinal cord. The occurrence of BSD is a longstanding problem in the American Brown Swiss (ABS) breed and in several European cattle breeds upgraded with ABS. Here, we show that the disease locus on bovine chromosome 11 harbors the SPAST gene that, when mutated, is responsible for the human disorder hereditary spastic paraplegia (HSP). Initially, SPAST encoding Spastin was considered a less likely candidate gene for BSD since the modes of inheritance as well as the time of onset and severity of symptoms differ widely between HSP and BSD. However, sequence analysis of the bovine SPAST gene in affected animals identified a R560Q substitution at a position in the ATPase domain of the Spastin protein that is invariant from insects to mammals. Interestingly, three different mutations in human SPAST gene at the equivalent position are known to cause HSP. To explore this observation further, we genotyped more than 3,100 animals of various cattle breeds and found that the glutamine allele exclusively occurred in breeds upgraded with ABS. Furthermore, all confirmed BSD carriers were heterozygous, while all affected calves were homozygous for the glutamine allele consistent with recessive transmission of the underlying mutation and complete penetrance in the homozygous state. Subsequent analysis of recombinant Spastin in vitro showed that the R560Q substitution severely impaired the ATPase activity, demonstrating a causal relationship between the SPAST mutation and BSD.

Tourette syndrome (TS) is a frequent neuropsychiatric disorder of unknown etiology. A number of chromosomal regions have been nominated as TS loci in linkage studies, but confirmation has met with limited success and causative mutations have not yet been definitely identified. Furthermore, TS, chronic tics, and obsessive-compulsive disorder (OCD) occur at increased frequencies among TS relatives, supporting the view that these phenotypes represent parts of the same genetically determined spectrum. We ascertained a four-generation Italian kindred segregating TS, chronic multiple motor tics (CMT), and OCD, and we performed a ten-centimorgan (cM) genome-wide linkage scan in order to map the underlying genetic defect. Suggestive linkage to chromosome 14q31.1 (multipoint LOD=2.4) was detected by affected-only analysis under an autosomal dominant model and a narrower phenotype definition (only the subjects with TS and CMT were considered as affected). The linkage peak increased and it approached genome-wide significance (LOD=3.29) when a broader phenotype definition was adopted (subjects with TS, CMT, and OCD considered as affected). Haplotype analysis defined a ∼2.3 cM critical region, shared by all the relatives with TS, CMT, or OCD. In conclusion, we provide strong evidence for linkage of TS spectrum to chromosome 14q31.1. Suggestive linkage to an overlapping region of chromosome 14q was reported in a recent scan of TS sibling pairs. This region might therefore contain an important gene for TS, and it should be prioritized for further study.

Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder preferentially affecting the longest corticospinal axons. More than 40 HSP genetic loci have been identified, among them SPG10, an autosomal dominant HSP caused by point mutations in the neuronal kinesin heavy chain protein KIF5A. Constitutive KIF5A knockout (KIF5A( -/- )) mice die early after birth. In these mice, lungs were unexpanded, and cell bodies of lower motor neurons in the spinal cord swollen, but the pathomechanism remained unclear. To gain insights into the pathophysiology, we characterized survival, outgrowth, and function in primary motor and sensory neuron cultures from KIF5A( -/- ) mice. Absence of KIF5A reduced survival in motor neurons, but not in sensory neurons. Outgrowth of axons and dendrites was remarkably diminished in KIF5A( -/- ) motor neurons. The number of axonal branches was reduced, whereas the number of dendrites was not altered. In KIF5A( -/- ) sensory neurons, neurite outgrowth was decreased but the number of neurites remained unchanged. In motor neurons maximum and average velocity of mitochondrial transport was reduced both in anterograde and retrograde direction. Our results point out a role of KIF5A in process outgrowth and axonal transport of mitochondria, affecting motor neurons more severely than sensory neurons. This gives pathophysiological insights into KIF5A associated HSP, and matches the clinical findings of predominant degeneration of the longest axons of the corticospinal tract.

The widely studied SH-SY5Y human neuroblastoma cell line provides a classic example of how a cancer cell line can be instrumental for discoveries of broad biological and clinical significance. An important feature of the SH-SY5Y cells is their ability to differentiate into a functionally mature neuronal phenotype. This property has conferred them the potential to be used as an in vitro model for studies of neurodegenerative and neurodevelopmental disorders. Here, we present a comprehensive assessment of the SH-SY5Y cytogenomic profile. Our results advocate for molecular cytogenetic data to inform the use of cancer cell lines in research.

We describe a family with an autosomal dominant familial dyskinesia resembling myoclonus-dystonia associated with a novel missense mutation in ADCY5, found through whole-exome sequencing. A tiered analytical approach was used to analyse whole-exome sequencing data from an affected grandmother-granddaughter pair. Whole-exome sequencing identified 18,000 shared variants, of which 46 were non-synonymous changes not present in a local cohort of control exomes (n = 422). Further filtering based on predicted splicing effect, minor allele frequency in the 1000 Genomes Project and on phylogenetic conservation yielded 13 candidate variants, of which the heterozygous missense mutation c.3086T>G, p. M1029R in ADCY5 most closely matched the observed phenotype. This report illustrates the utility of whole-exome sequencing in cases of undiagnosed movement disorders with clear autosomal dominant inheritance. Moreover, ADCY5 mutations should be considered in cases with apparent myoclonus-dystonia, particularly where SCGE mutations have been excluded. ADCY5-related dyskinesia may manifest variable expressivity within a single family, and affected individuals may be initially diagnosed with differing neurological phenotypes.

Here, we report brain white matter alterations in individuals clinically and genetically diagnosed with periodontal Ehlers-Danlos syndrome, a rare disease characterized by premature loss of teeth and connective tissue abnormalities. Eight individuals of two families clinically diagnosed with periodontal Ehlers-Danlos syndrome were included in the present study and underwent general physical, dental, and neurological examination. Whole exome sequencing was performed, and all patients included in the study underwent MRI of the brain. Whole exome sequencing revealed heterozygous C1R mutations c.926G>T (p.Cys309Phe, Family A) and c.149_150TC>AT (p.Val50Asp, Family B). All adult individuals (n = 7; age range 31 to 68 years) investigated by MRI had brain white matter abnormalities. The MRI of one investigated child aged 8 years was normal. The MRI pattern was suggestive of an underlying small vessel disease that is progressive with age. As observed in other leukoencephalopathies related to microangiopathies, the extent of the white matter changes was disproportionate to the neurologic features. Medical history revealed recurrent headaches or depression in some cases. Neurological examination was unremarkable in all individuals but one had mild cognitive decline and ataxia and experienced a seizure. The observation that periodontal Ehlers-Danlos syndrome caused by missense mutations in C1R is consistently associated with a leukoencephalopathy opens a new pathogenic link between the classical complement pathway, connective tissue, brain small vessels, and brain white matter abnormalities.

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.