Ataxia Genes Research Articles

Comprehensive Exonic Sequencing of Known Ataxia Genes in Episodic Ataxia.

Episodic Ataxias (EAs) are a small group (EA1–EA8) of complex neurological conditions that manifest as incidents of poor balance and coordination. Diagnostic testing cannot always find causative variants for the phenotype, however, and this along with the recently proposed EA type 9 (EA9), suggest that more EA genes are yet to be discovered. We previously identified disease-causing mutations in the CACNA1A gene in 48% (n = 15) of 31 patients with a suspected clinical diagnosis of EA2, and referred to our laboratory for CACNA1A gene testing, leaving 52% of these cases (n = 16) with no molecular diagnosis. In this study, whole exome sequencing (WES) was performed on 16 patients who tested negative for CACNA1A mutations. Tiered analysis of WES data was performed to first explore (Tier-1) the ataxia and ataxia-associated genes (n = 170) available in the literature and databases for comprehensive EA molecular genetic testing; we then investigated 353 ion channel genes (Tier-2). Known and potential causal variants were identified in n = 8/16 (50%) patients in 8 genes (SCN2A, p.Val1325Phe; ATP1A3, p.Arg756His; PEX7, p.Tyr40Ter; and KCNA1, p.Arg167Met; CLCN1, p.Gly945ArgfsX39; CACNA1E, p.Ile614Val; SCN1B, p.Cys121Trp; and SCN9A, p.Tyr1217Ter). These results suggest that mutations in these genes might cause an ataxia phenotype or that combinations of more than one mutation contribute to ataxia disorders.

Characterisation of canine KCNIP4: A novel gene for cerebellar ataxia identified by whole-genome sequencing two affected Norwegian Buhund dogs.

A form of hereditary cerebellar ataxia has recently been described in the Norwegian Buhund dog breed. This study aimed to identify the genetic cause of the disease. Whole-genome sequencing of two Norwegian Buhund siblings diagnosed with progressive cerebellar ataxia was carried out, and sequences compared with 405 whole genome sequences of dogs of other breeds to filter benign common variants. Nine variants predicted to be deleterious segregated among the genomes in concordance with an autosomal recessive mode of inheritance, only one of which segregated within the breed when genotyped in additional Norwegian Buhunds. In total this variant was assessed in 802 whole genome sequences, and genotyped in an additional 505 unaffected dogs (including 146 Buhunds), and only four affected Norwegian Buhunds were homozygous for the variant. The variant identified, a T to C single nucleotide polymorphism (SNP) (NC_006585.3:g.88890674T>C), is predicted to cause a tryptophan to arginine substitution in a highly conserved region of the potassium voltage-gated channel interacting protein KCNIP4. This gene has not been implicated previously in hereditary ataxia in any species. Evaluation of KCNIP4 protein expression through western blot and immunohistochemical analysis using cerebellum tissue of affected and control dogs demonstrated that the mutation causes a dramatic reduction of KCNIP4 protein expression. The expression of alternative KCNIP4 transcripts within the canine cerebellum, and regional differences in KCNIP4 protein expression, were characterised through RT-PCR and immunohistochemistry respectively. The voltage-gated potassium channel protein KCND3 has previously been implicated in spinocerebellar ataxia, and our findings suggest that the Kv4 channel complex KCNIP accessory subunits also have an essential role in voltage-gated potassium channel function in the cerebellum and should be investigated as potential candidate genes for cerebellar ataxia in future studies in other species.

The first biallelic missense mutation in the FXN gene in a consanguineous Turkish family with Charcot-Marie-Tooth-like phenotype.

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy with a prevalence of 1 in 2500 individuals worldwide. Here, we report three Turkish siblings from consanguineous parents presenting with a CMT-like phenotype who carry a homozygous c.493C>T, p.Arg165Cys mutation in the FXN gene that is the only known causative gene for Friedreich's ataxia (FRDA). The identified missense mutation has been reported previously in two FRDA cases in compound heterozygosity with the common GAA repeat expansion in the first intron of the FXN gene. Analysis of skin biopsy samples from our family indicated that the mutation does not affect the expression levels of the frataxin, pointing to functional impairment of the corresponding protein. The CMT phenotype in the siblings was associated with visual impairment, optic nerve atrophy, and dysarthria. To the best of our knowledge, this family represents the first FXN missense mutation in homozygosity and challenges the notion that missense mutations have not been reported yet due to their embryonic lethality. Furthermore, this finding poses an interesting genetic overlap between autosomal recessive CMT and FRDA that we believe may have important implications on understanding the pathogenesis of these neurological disorders.

A case of relapsing polychondritis with vestibular neuritis and cerebellar ataxia

Relapsing polychondritis(RP) is an autoimmune disease characterized by recurrent inflammatory episodes of cartilaginous structures. It is challenge to diagnosis RP, because it is established by clinical manifestations and the disease has diverse nature. We report interesting case, who had recurrent vertigo be seen as vestibular neuritis, diagnosed with RP. A 59-year-old male visited the emergency room with dizziness and ataxia. The symptom was recurrent from 6 months ago, six attacks were occurred. He also had 1-year history of swelling of both ear lobes. He felt repetitive vertigo and gait disturbance spontaneously recovered after few hours. Neurologic exam showed cerebellar ataxia and left spontaneous beating nystagmus. He showed right side deviation in past-pointing test. He had purplish erythema of both ear lobes, diagnosed as polychondritis. The VOG findings were compatible with vestibular neuritis. There were no specific findings on Brain MRI. In laboratory tests, RA was elevated, anticardiolipin Ab IgG was positive. Episodic ataxia gene was negative. In Seoul Neuropsychological Screening Battery, all domain functions were decreased. After treatment with high dose steroid and intravenous immunoglobulin treatment, neurologic deficit and chondritis were recovered. Relapsing polychondritis is a multisystemic autoimmune disorder. Neurological symptoms occur in minor cases but cerebellar symptoms could be presented. Cerebella ataxia could be seen in RP, but there were no vestibular neuritis cases by RP. In this case, the patient was clinically diagnosed as RP with recurrent chondritis of both auricles and vestibular neuritis with good response to immunosuppressive treatment. To confirm recurrent vertigo with RP, long term observation is needed.

PLS3 Overexpression Delays Ataxia in Chp1 Mutant Mice.

Many neurodegenerative disorders share common pathogenic pathways such as endocytic defects, Ca2+ misregulation and defects in actin dynamics. Factors acting on these shared pathways are highly interesting as a therapeutic target. Plastin 3 (PLS3), a proven protective modifier of spinal muscular atrophy across species, is a remarkable example of the former, and thereby offers high potential as a cross-disease modifier. Importantly, PLS3 has been linked to numerous proteins associated with various neurodegenerative diseases. Among them, PLS3 directly interacts with calcineurin like EF-hand protein 1 (CHP1), whose loss-of-function results in ataxia. In this study, we aimed to determine whether PLS3 is a cross-disease modifier for ataxia caused by Chp1 mutation in mice. For this purpose, we generated Chp1 mutant mice, named vacillator mice, overexpressing a PLS3 transgene. Here, we show that PLS3 overexpression (OE) delays the ataxic phenotype of the vacillator mice at an early but not later disease stage. Furthermore, we demonstrated that PLS3 OE ameliorates axon hypertrophy and axonal swellings in Purkinje neurons thereby slowing down neurodegeneration. Mechanistically, we found that PLS3 OE in the cerebellum shows a trend of increased membrane targeting and/or expression of Na+/H+ exchanger (NHE1), an important CHP1 binding partner and a causative gene for ataxia, when mutated in humans and mice. This data supports the hypothesis that PLS3 is a cross-disease genetic modifier for CHP1-causing ataxia and spinal muscular atrophy.

Genetic and phenotypic features of patients with childhood ataxias diagnosed by next-generation sequencing gene panel

BackgroundThe purpose of this prospective study was to identify the characteristics of pediatric recessive ataxias and the mutations leading to them. MethodsEighty-four pediatric patients aged 0–18 years presenting to our clinic, evaluated by means of imaging, metabolic or pathological investigation, or single-gene test, in whom Friedreich’s ataxia was excluded, and predicted to carry the progressive autosomal recessive ataxia gene were included in the study. Patients’ demographic, clinical, laboratory, and radiological characteristics were recorded. DNA and panel sequencing directed toward ataxia-related genes was performed using the next-generation sequencing method. ResultsA molecular diagnosis was established in 21 (25%) of the 84 patients. Genetically, infantile neuroaxonal dystrophy (7/21), ataxia with oculomotor apraxia type 1 (5/21), neuronal ceroid lipofuscinosis type 5 (2/21), ataxia with oculomotor apraxia type 2 (1/21), Lafora disease (1/21), tremor ataxia syndrome accompanying central hypomyelination (1/21), Charlevoix-Saguenay ataxia (1/21), Marinesco-Sjögren syndrome (1/21), VLDRL-associated cerebellar hypoplasia (1/21), and TSEN54-related pontocerebellar hypoplasia (1/21) mutations were detected. ConclusionsApproximately 25% of our patients were diagnosed. Novel mutations in the known genes were identified and are important in terms of phenotype-genotype correlation.

Expanding the Phenotype: Neurodevelopmental Disorder, Mitochondrial, With Abnormal Movements and Lactic Acidosis, With or Without Seizures (NEMMLAS) due to WARS2 Biallelic Variants, Encoding Mitochondrial Tryptophanyl-tRNA Synthase

WARS2 encodes a tryptophanyl tRNA synthetase, which is involved in mitochondrial protein synthesis. Biallelic mutations in WARS2 are rare and have been associated with a spectrum of clinical presentations, including neurodevelopmental disorder with abnormal movements, lactic acidosis with or without seizures (NEMMLAS). Here we present the case of an 8-year-old girl with ataxia and parkinsonism with periventricular white matter abnormalities on magnetic resonance imaging (MRI) and global developmental delay. The initial investigations revealed an elevated lactate level. Extensive metabolic testing, including a muscle biopsy, was inconclusive. Cerebrospinal fluid (CSF) neurotransmitter levels were low; however, a trial of levodopa was unremarkable. The chromosomal microarray and initial ataxia gene panel was normal. Zinc supplementation for a heterozygous variant of unknown significance in the CP gene on the ataxia exome panel was not effective in treating her symptoms. Reanalysis of the ataxia exome panel highlighted biallelic mutations in WARS2, which lead to the diagnosis of neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (NEMMLAS). This lead to parental genetic testing, redirected therapy, and helped to expand the symptomology of this rare condition. Here we emphasize the importance of imminent and repeat expanded genetic testing to ensure early diagnosis and treatment for rare pediatric disorders. The patient is being trialed on a mitochondrial cocktail in an attempt to compensate for defects in mitochondrial protein synthesis associated with this variant. Longitudinal monitoring of disease manifestation will help establish the currently unknown natural history of this condition.

Pathogenic variants in MT-ATP6: A United Kingdom-based mitochondrial disease cohort study.

Distinct clinical syndromes have been associated with pathogenic MT‐ATP6 variants. In this cohort study, we identified 125 individuals (60 families) including 88 clinically affected individuals and 37 asymptomatic carriers. Thirty‐one individuals presented with Leigh syndrome and 7 with neuropathy ataxia retinitis pigmentosa. The remaining 50 patients presented with variable nonsyndromic features including ataxia, neuropathy, and learning disability. We confirmed maternal inheritance in 39 families and demonstrated that tissue segregation patterns and phenotypic threshold are variant dependent. Our findings suggest that MT‐ATP6–related mitochondrial DNA disease is best conceptualized as a mitochondrial disease spectrum disorder and should be routinely included in genetic ataxia and neuropathy gene panels. ANN NEUROL 2019;86:310–315

Spinocerebellar ataxia with axonal neuropathy type 1 revisited

Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1; OMIM #607250), an exceedingly rare disorder having been documented in only a single family from Saudi Arabia, is the result of an unusual mutation in the tyrosyl DNA phosphodiesterase 1 gene (TDP1). We performed high-throughput sequencing (whole exome and ataxia gene panel) in two apparently unrelated Omani families segregating sensorimotor neuropathy and ataxia in an autosomal recessive fashion. Following validation by Sanger sequencing, all affected subjects (n = 4) were confirmed to carry the known SCAN1 pathogenic homozygous variant in the TDP1 gene, NM_001008744.1:c.1478A > G (p.His493Arg). In keeping with the initial description, our patients demonstrated progressive ataxia, cerebellar atrophy and disabling axonal sensori-motor neuropathy (n = 4), hypercholesterolemia (n = 2) and elevated serum alpha fetoprotein (n = 3). In addition, our patients also had mild cognitive deficits in multiple domains (n = 3), a feature not previously reported. Our findings independently revalidate the phenotype of TDP1 mutation and expand the clinical spectrum to include mild cognitive deficits. Haplotype sharing, as determined by DNA microarray (CytoScan HD), attests to a possible common founder mutation in the Arab population.

Next-generation sequencing study reveals the broader variant spectrum of hereditary spastic paraplegia and related phenotypes

Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurodegenerative disorders. Numerous genes linked to HSPs, overlapping phenotypes between HSP subtypes and other neurodegenerative disorders and the HSPs’ dual mode of inheritance (both dominant and recessive) make the genetic diagnosis of HSPs complex and difficult. Out of the original HSP cohort comprising 306 index cases (familial and isolated) who had been tested according to “traditional workflow/guidelines” by Multiplex Ligation-dependent Probe Amplification (MLPA) and Sanger sequencing, 30 unrelated patients (all familial cases) with unsolved genetic diagnoses were tested using next-generation sequencing (NGS). One hundred thirty-two genes associated with spastic paraplegias, hereditary ataxias and related movement disorders were analysed using the Illumina TruSight™ One Sequencing Panel. The targeted NGS data showed pathogenic variants, likely pathogenic variants and those of uncertain significance (VUS) in the following genes: SPAST (spastin, SPG4), ATL1 (atlastin 1, SPG3), WASHC5 (SPG8), KIF5A (SPG10), KIF1A (SPG30), SPG11 (spatacsin), CYP27A1, SETX and ITPR1. Out of the nine genes mentioned above, three have not been directly associated with the HSP phenotype to date. Considering the phenotypic overlap and joint cellular pathways of the HSP, spinocerebellar ataxia (SCA) and amyotrophic lateral sclerosis (ALS) genes, our findings provide further evidence that common genetic testing may improve the diagnostics of movement disorders with a spectrum of ataxia-spasticity signs.

A study in a Polish ataxia cohort indicates genetic heterogeneity and points to MTCL1 as a novel candidate gene.

Inherited ataxias are a group of highly heterogeneous, complex neurological disorders representing a significant diagnostic challenge in clinical practice. We performed a next-generation sequencing (NGS) analysis in 10 index cases with unexplained progressive cerebellar ataxia of suspected autosomal recessive inheritance. A definite molecular diagnosis was obtained in 5/10 families and included the following diseases: autosomal recessive spastic ataxia of Charlevoix-Saguenay, POLR3B-related hypomyelinating leukodystrophy, primary coenzyme Q10 deficiency type 4, Niemann-Pick disease type C1 and SYNE1-related ataxia. In addition, we found a novel homozygous MTCL1 loss of function variant p.(Lys407fs) in a 23-year-old patient with slowly progressive cerebellar ataxia, mild intellectual disability, seizures in childhood and episodic pain in the lower limbs. The identified variant is predicted to truncate the protein after first 444 of 1586 amino acids. MTCL1 encodes a microtubule-associated protein highly expressed in cerebellar Purkinje cells; its knockout in a mouse model causes ataxia. We propose MTCL1 as a candidate gene for autosomal recessive cerebellar ataxia in humans. In addition, our study confirms the high diagnostic yield of NGS in early-onset cerebellar ataxias, with at least 50% detection rate in our ataxia cohort.

Parkinsonism in neurodegenerative diseases predominantly presenting with ataxia.

The number of molecularly defined degenerative ataxia diseases is rapidly increasing, many of them involving complex multisystemic presentations including parkinsonism. The increasing number of novel ataxia genes -with most of them being ultra-rare - often makes it difficult for clinicians and scientists to identify the molecular diagnosis underlying these ataxia-parkinsonism syndromes. Here we aim to provide an overview on the most frequent diseases and molecular causes underlying ataxia-parkinsonism, focusing both on novel aspects of well-known causes of ataxia-parkinsonism (MSA-C, PSP-C, FXTAS, repeat-expansion spinocerebellar ataxias [SCAs], conventional mutation SCAs) as well as on more recently identified rare genetic causes of ataxia-parkinsonism (AT, POLG, SPG7). We demonstrate that frequency data and phenotype characteristics help to guide diagnostics in patients with unexplained ataxia-parkinsonism, while the newly identified rare genetic causes of ataxia-parkinsonism provide novel insights into molecular key pathways underlying the shared vulnerability of cerebellar and basal ganglia neurons.

Identification of novel compound heterozygous SPG7 mutations-related hereditary spastic paraplegia in a Chinese family: a case report

BackgroundAutosomal recessive hereditary spastic paraplegias (ARHSPs) are a group of clinically and genetically heterogeneous neurodegenerative diseases with progressive spasticity and weakness in the lower limbs. Mutations in the Spastic Paraplegia gene 7 (SPG7) account for about 5–21% of ARHSP cases. However, in Asians, few reports about the mutations exist. In this study, we firstly report a novel finding from a Chinese family with compound heterozygous SPG7 mutations, in which three siblings were affected with a complicated form of ARHSP.Case presentationA 56-year-old man presented with progressive stiffness, weakness and ataxia in the lower limbs. Two sisters of him had similar symptoms and dysarthria. Brain magnetic resonance imaging (MRI) revealed cerebellar atrophy in each of the patients. Genetic analysis, which exerted a targeted next generation sequencing (NGS) panel covering 917 comprehensive ataxia genes to the proband, followed by Sanger sequencing of candidate genes in other eight family members, was used to find the etiology of the disease. Ultimately, we identified compound heterozygous SPG7 mutations with two mutations: (c.1150_1150-1insCTAC and c.2062C > T, p.Arg688Trp) and one single nucleotide polymorphism (c.2063G > A, p.Arg688Gln).ConclusionsThe four bases insertion mutation (4bIM) was predicted to cause frameshift mutation or affect the splicing, and the last two variants were led to a stop codon mutation (p.Arg688Ter). As located in highly conserved positions and encoded paraplegin, the mutations were speculated to result in a truncated or defective protein and would be pathogenic factors of the disease. This paper proves to be the first case report of SPG7 mutation in ARHSP reported in Chinese population. Our findings widen the spectrum of SPG7 mutations of ARHSP and indicate that the SPG7 mutation is an important cause of adult-onset undiagnosed ataxia.

Progressive myoclonus ataxia: Time for a new definition?

ABSTRACT Background: The clinical demarcation of the syndrome progressive myoclonus ataxia is unclear, leading to a lack of recognition and difficult differentiation from other neurological syndromes. Objectives: The objective of this study was to apply a refined definition of progressive myoclonus ataxia and describe the clinical characteristics in patients with progressive myoclonus ataxia and with isolated cortical myoclonus. Methods: A retro‐ and prospective analysis was performed in our tertiary referral center between 1994 and 2014. Inclusion criteria for progressive myoclonus ataxia patients were the presence of myoclonus and ataxia with or without infrequent (all types, treatment responsive) epileptic seizures. Inclusion criteria for isolated cortical myoclonus was the presence of isolated cortical myoclonus. Clinical and electrophysiological characteristics data were systematically scored. Results: A total of 14 progressive myoclonus ataxia patients (males, 7; females, 7), median age 14.5 years, and 8 isolated cortical myoclonus patients (males, 2; females, 6), median age 23.5 years, were identified. In 93% of the progressive myoclonus ataxia patients, ataxia started first (median 2 years) followed by myoclonus (4 years) and finally infrequent epilepsy (9.3 years), with a progressive course in 93%. In 64% of the progressive myoclonus ataxia patients, a genetic underlying etiology was identified, including 3 not earlier reported causative progressive myoclonus ataxia genes. In isolated cortical myoclonus patients, myoclonus started at (median) 12 years with progression over time in 63% and a single epileptic seizure in 1 patient. No genetic causes were identified. Conclusion: Using a refined definition, we could create a rather homogenous progressive myoclonus ataxia group. Patients with isolated cortical myoclonus have a different course and do not appear to evolve in progressive myoclonus ataxia. The refined progressive myoclonus ataxia definition is a successful first step toward creating a separate syndrome for both clinical practice and future genetic research. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Collaborative science unites researchers and a novel spastic ataxia gene.

Annals of NeurologyVolume 83, Issue 6 p. 1072-1074 Invited Commentarie Collaborative science unites researchers and a novel spastic ataxia gene Brent L. Fogel MD, PhD, Brent L. Fogel MD, PhD Departments of Neurology and Human Genetics David Geffen School of Medicine, University of California, Los Angeles Los Angeles, CASearch for more papers by this author Brent L. Fogel MD, PhD, Brent L. Fogel MD, PhD Departments of Neurology and Human Genetics David Geffen School of Medicine, University of California, Los Angeles Los Angeles, CASearch for more papers by this author First published: 16 June 2018 https://doi.org/10.1002/ana.25262Citations: 4Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume83, Issue6June 2018Pages 1072-1074 RelatedInformation

Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known Cerebellar Ataxia Genes

Molecular diagnosis is difficult to achieve in disease groups with a highly heterogeneous genetic background, such as cerebellar ataxia (CA). In many patients, candidate gene sequencing or focused resequencing arrays do not allow investigators to reach a genetic conclusion. To assess the efficacy of exome-targeted capture sequencing to detect mutations in genes broadly linked to CA in a large cohort of undiagnosed patients and to investigate their prevalence. Three hundred nineteen index patients with CA and without a history of dominant transmission were included in the this cohort study by the Spastic Paraplegia and Ataxia Network. Centralized storage was in the DNA and cell bank of the Brain and Spine Institute, Salpetriere Hospital, Paris, France. Patients were classified into 6 clinical groups, with the largest being those with spastic ataxia (ie, CA with pyramidal signs [n = 100]). Sequencing was performed from January 1, 2014, through December 31, 2016. Detected variants were classified as very probably or definitely causative, possibly causative, or of unknown significance based on genetic evidence and genotype-phenotype considerations. Identification of variants in genes broadly linked to CA, classified in pathogenicity groups. The 319 included patients had equal sex distribution (160 female [50.2%] and 159 male patients [49.8%]; mean [SD] age at onset, 27.9 [18.6] years). The age at onset was younger than 25 years for 131 of 298 patients (44.0%) with complete clinical information. Consanguinity was present in 101 of 298 (33.9%). Very probable or definite diagnoses were achieved for 72 patients (22.6%), with an additional 19 (6.0%) harboring possibly pathogenic variants. The most frequently mutated genes were SPG7 (n = 14), SACS (n = 8), SETX (n = 7), SYNE1 (n = 6), and CACNA1A (n = 6). The highest diagnostic rate was obtained for patients with an autosomal recessive CA with oculomotor apraxia-like phenotype (6 of 17 [35.3%]) or spastic ataxia (35 of 100 [35.0%]) and patients with onset before 25 years of age (41 of 131 [31.3%]). Peculiar phenotypes were reported for patients carrying KCND3 or ERCC5 variants. Exome capture followed by targeted analysis allows the molecular diagnosis in patients with highly heterogeneous mendelian disorders, such as CA, without prior assumption of the inheritance mode or causative gene. Being commonly available without specific design need, this procedure allows testing of a broader range of genes, consequently describing less classic phenotype-genotype correlations, and post hoc reanalysis of data as new genes are implicated in the disease.

Protein kinase C activity is a protective modifier of Purkinje neuron degeneration in cerebellar ataxia.

Among the many types of neurons expressing protein kinase C (PKC) enzymes, cerebellar Purkinje neurons are particularly reliant on appropriate PKC activity for maintaining homeostasis. The importance of PKC enzymes in Purkinje neuron health is apparent as mutations in PRKCG (encoding PKCγ) cause cerebellar ataxia. PRKCG has also been identified as an important node in ataxia gene networks more broadly, but the functional role of PKC in other forms of ataxia remains unexplored, and the mechanisms by which PKC isozymes regulate Purkinje neuron health are not well understood. Here, we investigated how PKC activity influences neurodegeneration in inherited ataxia. Using mouse models of spinocerebellar ataxia type 1 (SCA1) and 2 (SCA2) we identify an increase in PKC-mediated substrate phosphorylation in two different forms of inherited cerebellar ataxia. Normalizing PKC substrate phosphorylation in SCA1 and SCA2 mice accelerates degeneration, suggesting that the increased activity observed in these models is neuroprotective. We also find that increased phosphorylation of PKC targets limits Purkinje neuron membrane excitability, suggesting that PKC activity may support Purkinje neuron health by moderating excitability. These data suggest a functional role for PKC enzymes in ataxia gene networks, and demonstrate that increased PKC activity is a protective modifier of degeneration in inherited cerebellar ataxia.

Chapter 13 - Autosomal-recessive cerebellar ataxias

The autosomal-recessive cerebellar ataxias comprise more than half of the known genetic forms of ataxia and represent an extensive group of clinically heterogeneous disorders that can occur at any age but whose onset is typically prior to adulthood. In addition to ataxia, patients often present with polyneuropathy and clinical symptoms outside the nervous system. The most common of these diseases is Friedreich ataxia, caused by mutation of the frataxin gene, but recent advances in genetic analysis have greatly broadened the ever-expanding number of causative genes to over 50. In this review, the clinical neurogenetics of the recessive cerebellar ataxias will be discussed, including updates on recently identified novel ataxia genes, advancements in unraveling disease-specific molecular pathogenesis leading to ataxia, potential treatments under development, technologic improvements in diagnostic testing such as clinical exome sequencing, and what the future holds for clinicians and geneticists.

Chapter 10 - Spinocerebellar ataxias

There are over 40 autosomal dominant spinocerebellar ataxias (SCAs) now identified. In this chapter we delineate the phenotypes of SCAs 1-44 and dentatorubral-pallidoluysian atrophy (DRPLA) and highlight the clinical and genetic features of the well characterised SCAs in detail in the main section of the chapter, along with their frequency and age at onset. We have included a section on the key phenotypic features of rare spinocerebellar ataxias and discuss rare and unusual presentations and genetic mechanisms of the ataxias and show differences between adult and paediatric presentations. We look at unusual mechanisms where knowledge is evolving in some dominant ataxias. For ease of reference we have tabulated historical aspects of the ataxias, major neurological diagnostic features, ataxias with predominant paediatric and infantile onset and list recognisable nerve conduction features. We comment on the anti-sense ataxia gene mechanisms and we discuss potential developments including exome sequencing and potential therapeutic options. A gene table listing all of the identified SCAs and DRPLA is also included with key references and gene locations and symbols with OMIM reference numbers for further reading.

Postural Tremor and Ataxia Progression in Spinocerebellar Ataxias.

BackgroundPostural tremor can sometimes occur in spinocerebellar ataxias (SCAs). However, the prevalence and clinical characteristics of postural tremor in SCAs are poorly understood, and whether SCA patients with postural tremor have different ataxia progression is not known.MethodsWe studied postural tremor in 315 patients with SCA1, 2, 3, and 6 recruited from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA), which consists of 12 participating centers in the United States, and we evaluated ataxia progression in these patients from January 2010 to August 2012.ResultsAmong 315 SCA patients, postural tremor was most common in SCA2 patients (SCA1, 5.8%; SCA2, 27.5%; SCA3, 12.4%; SCA6, 16.9%; p = 0.007). SCA3 patients with postural tremor had longer CAG repeat expansions than SCA3 patients without postural tremor (73.67 ± 3.12 vs. 70.42 ± 3.96, p = 0.003). Interestingly, SCA1 and SCA6 patients with postural tremor had a slower rate of ataxia progression (SCA1, β = –0.91, p < 0.001; SCA6, β = –1.28, p = 0.025), while SCA2 patients with postural tremor had a faster rate of ataxia progression (β = 1.54, p = 0.034). We also found that the presence of postural tremor in SCA2 patients could be influenced by repeat expansions of ATXN1 (β = –1.53, p = 0.037) and ATXN3 (β = 0.57, p = 0.018), whereas postural tremor in SCA3 was associated with repeat lengths in TBP (β = 0.63, p = 0.041) and PPP2R2B (β = –0.40, p = 0.032).DiscussionPostural tremor could be a clinical feature of SCAs, and the presence of postural tremor could be associated with different rates of ataxia progression. Genetic interactions between ataxia genes might influence the brain circuitry and thus affect the clinical presentation of postural tremor.