Progressive Spinocerebellar Ataxia Research Articles

Biallelic mutation of HSD17B4 induces middle age-onset spinocerebellar ataxia.

ObjectiveTo determine the genetic underpinnings of slowly progressive spinocerebellar ataxia, autosomal recessive (SCAR), we performed exome analysis and examined the relationship between clinical severity and functional change induced by the mutation.MethodsHomozygosity fingerprinting and exome sequencing were performed to identify causative mutations in 2 consanguineous families. We assessed the expression of D-bifunctional protein (DBP) and the amount of dimerized DBP in fibroblasts by immunoblot and quantitative reverse transcription PCR. The pathogenicity of the mutation was evaluated using the Combined Annotation-Dependent Depletion (CADD) scores; these results were compared with the scores of previously reported mutations.ResultsWe identified a homozygous mutation as causative of middle age–onset SCAR: p.Ala175Thr, which is located in HSD17B4 that encodes peroxisomal DBP. The patients developed cerebellar ataxia, and the subsequent progression was slow. The symptoms presented were milder than those in previously reported cases. The messenger RNA expression levels were normal, but protein levels were diminished. Dimerization of DBP was also reduced. The CADD score of the identified mutation was lower than those of previously reported mutations.ConclusionsThis is the report of middle age–onset DBP deficiency. Residual functional DBP caused relatively mild symptoms in the affected patients, i.e., slowly progressive ataxia and hearing loss. This study broadens the scope of DBP deficiency phenotypes and indicates that CADD scores may be used to estimate the severity of DBP deficiencies.

Primary Cultures of Pure Embryonic Dorsal Root Ganglia Sensory Neurons as a New Cellular Model for Friedreich's Ataxia.

Peripheral neuropathies can have various origins, from genetic to acquired causes, and affect altogether a large group of people in the world. Current available therapies aim at helping the disease symptoms but not to correct or stop the development of the disease. Primary neuronal cultures represent an essential tool in the study of events related to peripheral neuropathies as they allow to isolate the affected cell types, often originating in complex tissues in which they account for only a few percentage of cells. They provide a powerful system to identifying or testing compounds with potential therapeutic effect in the treatment of those diseases. Friedreich's ataxia is an autosomal recessive neurodegenerative disorder, which is characterized by a progressive spinocerebellar and sensory ataxia. Proprioceptive neurons of the dorsal root ganglia (DRG) are the primary affected cells. The disease is triggered by a mutation in the gene FXN which leads to a reduction of the frataxin protein. In order to study the neurophysiopathology of the disease at the cellular and molecular levels, we have established a model of primary cultures of DRG sensory neurons in which we induce the loss of the frataxin protein. With such a model we can alleviate the issues related to the complexity of DRG tissues and low amount of sensory neuron material in adult mouse. Hereby, we provide a protocol of detailed and optimized methods to obtain high yield of healthy mouse DRG sensory neuron in culture.

Truncating SLC12A6 variants cause different clinical phenotypes in humans and dogs.

Clinical, pathological, and genetic findings of a primary hereditary ataxia found in a Malinois dog family are described and compared with its human counterpart. Based on the family history and the phenotype/genotype relationships already described in humans and dogs, a causal variant was expected to be found in KCNJ10. Rather surprisingly, whole-exome sequencing identified the SLC12A6 NC_006612.3(XM_014109414.2): c.178_181delinsCATCTCACTCAT (p.(Met60Hisfs*14)) truncating variant. This loss-of-function variant perfectly segregated within the affected Malinois family in an autosomal recessive way and was not found in 562 additional reference dogs from 18 different breeds, including Malinois. In humans, SLC12A6 variants cause "agenesis of the corpus callosum with peripheral neuropathy" (ACCPN, alias Andermann syndrome), owing to a dysfunction of this K+-Cl- cotransporter. However, depending on the variant (including truncating variants), different clinical features are observed within ACCPN. The variant in dogs encodes the shortest isoform described so far and its resultant phenotype is quite different from humans, as no signs of peripheral neuropathy, agenesis of the corpus callosum nor obvious mental retardation have been observed in dogs. On the other hand, progressive spinocerebellar ataxia, which is the most important feature of the canine phenotype, hindlimb paresis, and myokymia-like muscle contractions have not been described in humans with ACCPN so far. As this is the first report of a naturally occurring disease-causing SLC12A6 variant in a non-human species, the canine model will be highly valuable to better understand the complex molecular pathophysiology of SLC12A6-related neurological disorders and to evaluate novel treatment strategies.

Diminished OPA1 expression and impaired mitochondrial morphology and homeostasis in Aprataxin-deficient cells.

Ataxia with oculomotor apraxia type 1 (AOA1) is an early onset progressive spinocerebellar ataxia caused by mutation in aprataxin (APTX). APTX removes 5'-AMP groups from DNA, a product of abortive ligation during DNA repair and replication. APTX deficiency has been suggested to compromise mitochondrial function; however, a detailed characterization of mitochondrial homeostasis in APTX-deficient cells is not available. Here, we show that cells lacking APTX undergo mitochondrial stress and display significant changes in the expression of the mitochondrial inner membrane fusion protein optic atrophy type 1, and components of the oxidative phosphorylation complexes. At the cellular level, APTX deficiency impairs mitochondrial morphology and network formation, and autophagic removal of damaged mitochondria by mitophagy. Thus, our results show that aberrant mitochondrial function is a key component of AOA1 pathology. This work corroborates the emerging evidence that impaired mitochondrial function is a characteristic of an increasing number of genetically diverse neurodegenerative disorders.

Mitochondrial PITRM1 peptidase loss-of-function in childhood cerebellar atrophy

ObjectiveTo identify the genetic basis of a childhood-onset syndrome of variable severity characterised by progressive spinocerebellar ataxia, mental retardation, psychotic episodes and cerebellar atrophy.MethodsIdentification of the underlying mutations by whole...

Parkinson\u2019s disease associated with pure ATXN10 repeat expansion

Large, non-coding pentanucleotide repeat expansions of ATTCT in intron 9 of the ATXN10 gene typically cause progressive spinocerebellar ataxia with or without seizures and present neuropathologically with Purkinje cell loss resulting in symmetrical cerebellar atrophy. These ATXN10 repeat expansions can be interrupted by sequence motifs which have been attributed to seizures and are likely to act as genetic modifiers. We identified a Mexican kindred with multiple affected family members with ATXN10 expansions. Four affected family members showed clinical features of spinocerebellar ataxia type 10 (SCA10). However, one affected individual presented with early-onset levodopa-responsive parkinsonism, and one family member carried a large repeat ATXN10 expansion, but was clinically unaffected. To characterize the ATXN10 repeat, we used a novel technology of single-molecule real-time (SMRT) sequencing and CRISPR/Cas9-based capture. We sequenced the entire span of ~5.3–7.0 kb repeat expansions. The Parkinson’s patient carried an ATXN10 expansion with no repeat interruption motifs as well as an unaffected sister. In the siblings with typical SCA10, we found a repeat pattern of ATTCC repeat motifs that have not been associated with seizures previously. Our data suggest that the absence of repeat interruptions is likely a genetic modifier for the clinical presentation of l-Dopa responsive parkinsonism, whereas repeat interruption motifs contribute clinically to epilepsy. Repeat interruptions are important genetic modifiers of the clinical phenotype in SCA10. Advanced sequencing techniques now allow to better characterize the underlying genetic architecture for determining accurate phenotype–genotype correlations.

Autosomal recessive cerebellar ataxia caused by a homozygous mutation inPMPCA

Sir, Recently, Jobling et al. (2015) reported the identification of mutations in PMPCA in 17 patients from four families affected with autosomal recessive non-progressive cerebellar ataxia. A homozygous missense mutation in PMPCA (c.1129G>A, p.Ala377Thr) was uncovered in three families of Christian Lebanese Maronite origin, while compound heterozygous mutations (c.287C>T, p.Ser96Leu; c.1543G>A, p.Gly515Arg) were identified in a French patient (Jobling et al. , 2015). PMPCA encodes the alpha subunit of the mitochondrial processing peptidase (MPP), which cleaves the targeting peptide of nuclear-encoded mitochondrial precursor proteins upon their import into mitochondria (Teixeira and Glaser, 2013). Jobling et al. (2015) showed compelling evidence for the causality of PMPCA variants. First, they demonstrated co-segregation of the variants with the disease among the four families, including a large consanguineous family of 32 individuals. Moreover, they observed decreased levels of MPPα in lymphoblasts from two affected members compared to heterozygote carriers and healthy controls. Interestingly, they also showed impaired processing of frataxin (FXN), a mitochondrial protein that is a known substrate of MPP (Cavadini et al. , 2000; Schmucker et al. , 2008). The paper by Jobling et al. (2015) is the first to associate defects in PMPCA with a human disease, which suggests a new mechanism for the pathogenesis of non-progressive cerebellar ataxias. We wish to complement this study with our own identification of two brothers affected by a juvenile-onset recessive cerebellar ataxia caused by a homozygous mutation in PMPCA . These two patients were born of French Canadian parents who are distantly related (Fig. 1A). Considerable clinical variability was present between the two affected cases. Patient II.2 started developing impaired gait, dysarthria, dysmetria and mild distal atrophy during adolescence. He was diagnosed with a slowly progressive spinocerebellar ataxia. He did not have intellectual deficiency but had learning difficulties in school. Patient II.3 …

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.

CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of CaV2.1 channels function, presumably affecting cerebellar, cortical and limbic networks.

Neuropathy target esterase impairments cause Oliver–McFarlane and Laurence–Moon syndromes

BackgroundOliver–McFarlane syndrome is characterised by trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy. Laurence–Moon syndrome presents similarly, though with progressive spinocerebellar ataxia and spastic paraplegia and without trichomegaly. Both...

Chlorophyllin: A possible new therapeutic agent for increasing frataxin levels in Friedreich'/INS;s ataxia patients

FRDA is an autosomal recessive neurodegenerative disease characterized by multiple symptoms such as progressive spinocerebellar ataxia, sensory nerve affection,diabetesmellitus andlife-limitinghypertrophic cardiomyopathy. FRDA is caused by a GAA-trinucleotide expansion in the frataxin gene located on chromosome locus 9q13 which results in a markedly reduced expressionof frataxin, a smallmitochondrialprotein. Decreased frataxin levels cause iron accumulation in mitochondria, oxidative stress and cell damage. Searching for compounds which could possibly influence frataxin expression we found that the chlorophyllins can significantly increase frataxin expression by still an unknown mechanism. Chlorophyllin (CHL) is a water-soluble mixtureof salts of the green plant pigment chlorophyll. CHL currently has a wide range of uses, dietary and medicinal, including being a food colouring agent, a health food additive, an accelerant of wound healing and controlling urinary and faecal odours in geriatric patients. In a wide array of in vitro and in vivo assays, CHL has also been shown to exhibit antimutagenic, antigenotoxic and anticarcinogenic activities against numerous carcinogens. We show for the first time that additional to its protective properties chlorophyllin can increase frataxin expression in vitro and in vivo. Our results provide a scientific basis for a clinical pilot trial examining the effectiveness of this agent for the treatment of FRDA patients.

Quetiapine Treatment for Psychosis in Friedreich's Ataxia

Friedreich's Ataxia is the most common form of progressive spinocerebellar ataxia with mixed sensory and cerebellar components and is inherited via an autosomal-recessive gene. Cognitive impairment, depression, emotional lability, and schizophrenialike psychosis are the psychiatric manifestations of the disease. In this study we describe a patient with Friedreich's ataxia who developed psychosis and responded to quetiapine.

Video game–based coordinative training improves ataxia in children with degenerative ataxia

Degenerative ataxias in children present a rare condition where effective treatments are lacking. Intensive coordinative training based on physiotherapeutic exercises improves degenerative ataxia in adults, but such exercises have drawbacks for children, often including a lack of motivation for high-frequent physiotherapy. Recently developed whole-body controlled video game technology might present a novel treatment strategy for highly interactive and motivational coordinative training for children with degenerative ataxias. We examined the effectiveness of an 8-week coordinative training for 10 children with progressive spinocerebellar ataxia. Training was based on 3 Microsoft Xbox Kinect video games particularly suitable to exercise whole-body coordination and dynamic balance. Training was started with a laboratory-based 2-week training phase and followed by 6 weeks training in children's home environment. Rater-blinded assessments were performed 2 weeks before laboratory-based training, immediately prior to and after the laboratory-based training period, as well as after home training. These assessments allowed for an intraindividual control design, where performance changes with and without training were compared. Ataxia symptoms were significantly reduced (decrease in Scale for the Assessment and Rating of Ataxia score, p = 0.0078) and balance capacities improved (dynamic gait index, p = 0.04) after intervention. Quantitative movement analysis revealed improvements in gait (lateral sway: p = 0.01; step length variability: p = 0.01) and in goal-directed leg placement (p = 0.03). Despite progressive cerebellar degeneration, children are able to improve motor performance by intensive coordination training. Directed training of whole-body controlled video games might present a highly motivational, cost-efficient, and home-based rehabilitation strategy to train dynamic balance and interaction with dynamic environments in a large variety of young-onset neurologic conditions. This study provides Class III evidence that directed training with Xbox Kinect video games can improve several signs of ataxia in adolescents with progressive ataxia as measured by SARA score, Dynamic Gait Index, and Activity-specific Balance Confidence Scale at 8 weeks of training.

Case of Infantile Onset Spinocerebellar Ataxia Type 5

Dominant spinocerebellar ataxias are a rare clinically and genetically heterogeneous group of neurodegenerative disorders. They are characterized by progressive cerebellar ataxia resulting in unsteady gait, clumsiness, dysarthria, and swallowing difficulty. The onset of symptoms is usually in the third or fourth decade of life; however, more subtle clinical manifestations can start in early childhood. Spinocerebellar ataxia type 5, a dominant spinocerebellar ataxia associated with mutations involving β-III spectrin (SPTBN2), has been described in 3 families. It typically consists of a slowly progressive spinocerebellar ataxia with onset in the third decade. The authors present the first case of infantile-onset spinocerebellar ataxia associated with a novel SPTBN2 mutation (transition C>T at nucleotide position 1438), the proband having a much more severe phenotype with global developmental delay, hypotonia, tremor, nystagmus, and facial myokymia.

Transcriptional regulation of the Tocopherol Transfer Protein

Vitamin E is a family of neutral plant lipids of which RRR α‐tocopherol (tocopherol) is selectively retained in the body and thus is considered the most biologically active form. Tocopherol's ability to scavenge free radicals defines tocopherol as the major lipid‐soluble antioxidant in humans. Tocopherol's essential function in humans has been recognized for decades, as well as its specific role in protecting cells from oxidative stress‐related damage. Low tocopherol levels were found to associate with increased risk for oxidative stress‐related diseases, like Alzheimer's and cardiovascular disease. Tocopherol transfer protein (TTP) is a cytosolic protein that facilitates intracellular transfer of tocopherol and maintains whole body vitamin E status. Mutations in TTP result in the heritable disease ataxia with vitamin E deficiency (AVED; OMIM #600415), characterized by progressive spinocerebellar ataxia and very low vitamin E levels. Despite the well‐documented role of TTP in maintaining normal tocopherol status, the mechanisms that regulate transcription of the TTPA gene are unknown. Our study found that expression of the TTPA gene in immortalized human hepatocytes is significantly enhanced upon treatment with chemical agonists of the transcription factors PPARδ, RXR, and CREB, as well as by H2O2 and a hypoxia mimetic. We also cloned a 2 Kb proximal region of the human TTP promoter, and used it to drive expression of a reporter construct. Promoter “bashing” experiments revealed distinct sites of transcriptional repression and activation. Finally, we show that single nucleotide polymorphisms (SNPs) have profound impact on the transcriptional activity of the cloned TTP promoter. These findings may explain altered responses to vitamin E supplementation in human clinical trials. Taken together, our results suggest that TTP is indeed transcriptionally regulated and this regulation may have a profound effect on vitamin E status in humans.Grant Funding Source : T32DK07319 and RO1DK067494

Fibroblast growth factor homologous factor 1 interacts with NEMO to regulate NF-κB signaling in neurons

Neuronal survival and plasticity critically depend on constitutive activity of the transcription factor nuclear factor-κB (NF-κB). We here describe a role for a small intracellular fibroblast growth factor homologue, the fibroblast growth factor homologous factor 1 (FHF1/FGF12), in the regulation of NF-κB activity in mature neurons. FHFs have previously been described to control neuronal excitability, and mutations in FHF isoforms give rise to a form of progressive spinocerebellar ataxia. Using a protein-array approach, we identified FHF1b as a novel interactor of the canonical NF-κB modulator IKKγ/NEMO. Co-immunoprecipitation, pull-down and GAL4-reporter experiments, as well as proximity ligation assays, confirmed the interaction of FHF1 and NEMO and demonstrated that a major site of interaction occurred within the axon initial segment. Fhf1 gene silencing strongly activated neuronal NF-κB activity and increased neurite lengths, branching patterns and spine counts in mature cortical neurons. The effects of FHF1 on neuronal NF-κB activity and morphology required the presence of NEMO. Our results imply that FHF1 negatively regulates the constitutive NF-κB activity in neurons.

Hypergonadotropic Hypogonadism, Progressive Early-Onset Spinocerebellar Ataxia, and Late-Onset Sensorineural Hearing Loss: Case Report and Literature Review

The association of ataxia, hypergonadotropic hypogonadism and hearing loss is extremely rare. Considerable heterogeneity exists in the literature of the neurological manifestations, age of onset, clinical severity and associated abnormalities. We describe a 24-year-old woman with secondary hypergonadotropic amenorrhea, early-onset progressive spinocerebellar ataxia (SCA), late-onset sensorineural hearing loss and normal intelligence and compare it with reported cases.

Progressive spinocerebellar ataxia mimicked by a presumptive cerebellar arteriovenous malformation

Here we report the case of a 72-year-old woman who presented with severe progressive ataxia over 32 years clinically thought to be due to a hereditary neurodegenerative disease, spinocerebellar ataxia. Magnetic resonance imaging with diffusion tensor imaging revealed a presumed arteriovenous malformation in the left cerebellar hemisphere, based on evidence of prior bleeding, resulting in asymmetrical atrophy of the cerebellum and brainstem not consistent with a primary cerebellar neurodegenerative process. This is the first report of an arteriovenous malformation insidiously mimicking a progressive spinocerebellar ataxia.

Slowly progressive spinocerebellar ataxia with extrapyramidal signs and mild cognitive impairment (SCA21)

Spinocerebellar ataxia 21 is a slowly progressive and mild ataxia associated with extrapyramidal signs. Affected subjects exhibit a moderate gait and limb ataxia variably associated with akinesia, tremor, rigidity, hyporeflexia, and mild cognitive impairment. The responsible gene has been assigned to a 19 Mbases interval on chromosome 7p in a single French family. No evidence of significant linkage to this locus was found in 21 other families obtained from the EUROSCA consortium. The locus interval contains several candidate genes that could be responsible for the disease. Direct sequencing of NDUFA4, PHF14, KIAA0960, ARLA4, ETV1, DGKB, HDAC9, FERD3L, ITGB8, and SP4 genes were performed, but all the direct mutation analyses were negative excluding pathogenic mutations associated with the disease. Therefore, the gene responsible for SCA21 remains to be identified.

Impaired hippocampal synaptic transmission and plasticity in mice lacking fibroblast growth factor 14

Humans with an autosomal dominant missense mutation in fibroblast growth factor 14 (FGF14) have impaired cognitive abilities and slowly progressive spinocerebellar ataxia. To explore the mechanisms that may account for this phenotype, we show that synaptic transmission at hippocampal Schaffer collateral-CA1 synapses and short- and long-term potentiation are impaired in Fgf14 −/− mice, indicating abnormalities in synaptic plasticity. Examination of CA1 synapses in Fgf14 −/− mice show a significant reduction in the number of synaptic vesicles docked at presynaptic active zones and a significant synaptic fatigue/depression during high/low-frequency stimulation. In addition, mEPSC frequency, but not amplitude, is decreased in hippocampal neurons derived from Fgf14 −/− mice. Furthermore, expression of selective synaptic proteins in Fgf14 −/− mice was decreased. These findings suggest a novel role for FGF14 in regulating synaptic plasticity via presynaptic mechanisms by affecting the mobilization, trafficking, or docking of synaptic vesicles to presynaptic active zones.

Slowly progressive spinocerebellar ataxia with extrapyramidal signs and mild cognitive impairment (SCA21)

Slowly progressive spinocerebellar ataxia with extrapyramidal signs and mild cognitive impairment (SCA21)