Autosomal Recessive Ataxia Research Articles

Spinocerebellar ataxia 48 presenting with ataxia associated with cognitive, psychiatric, and extrapyramidal features: A report of two Italian families

IntroductionSpinocerebellar ataxia 48 has recently been described as an adult onset ataxia associated with a cerebellar cognitive affective syndrome, caused by a heterozygous mutation in the STUB1 gene. MethodsWe characterized the clinical and neuroimaging phenotype of eight patients from two autosomal dominant ataxia multigenerational Italian families, in whom we conducted whole exome sequencing, targeted multigene sequencing, and Sanger sequencing studies. ResultsWe describe a complex syndrome characterized by ataxia and cognitive-psychiatric disorder in all cases, variably associated with chorea, parkinsonism, dystonia, urinary symptoms, and epilepsy. MRI showed a significant cerebellar atrophy, coupled to a T2-weighted hyperintensity affecting the dentate nuclei and extending to the middle cerebellar peduncles, whereas FDG-PET studies revealed glucose hypometabolism in cerebellum, striatum, and cerebral cortex.We identified two different novel STUB1 mutations segregating in the two families. One of the two mutations, p.(Gly33Ser), occurs in the TRP domain, whereas p.(Pro228Ser) is located in the ubiquitin ligase region. DiscussionWe emphasize the similarity of the described clinical picture with that of SCAR16, an autosomal recessive ataxia caused by biallelic mutations in the same gene, and of spinocerebellar ataxia type 17, which is considered the main Huntington's disease-like syndrome. The pathogenesis of the disease and the relationship between SCA48 and SCAR16 remain to be clarified.

Exome sequencing found a novel homozygous deletion in ADCK3 gene involved in autosomal recessive spinocerebellar ataxia

Autosomal recessive cerebellar ataxia is heterogeneous inherited neurodegenerative disorders with more than 70 involved genes. The development of next generation sequencing opens a new window in rapid diagnosis of such heterogeneous condition in medical genetics laboratories. Here, we present ADCK3; del.CD (229–230) mutation in an Iranian consanguineous family with three cerebellar ataxic boys using whole exome sequencing. The mutation was predicted pathogenic and all the affected individuals were homozygous for the variant. Although, the ADCK3 was previously reported as one of the master genes of ARSC, our mutation was novel as has been not previously reported in dbSNP or literature.

Primary Coenzyme Q deficiency Due to Novel ADCK3 Variants, Studies in Fibroblasts and Review of Literature.

Primary deficiency of coenzyme Q10 (CoQ10 ubiquinone), is classified as a mitochondrial respiratory chain disorder with phenotypic variability. The clinical manifestation may involve one or multiple tissue with variable severity and presentation may range from infancy to late onset. ADCK3 gene mutations are responsible for the most frequent form of hereditary CoQ10 deficiency (Q10 deficiency-4 OMIM #612016) which is mainly associated with autosomal recessive spinocerebellar ataxia (ARCA2, SCAR9). Here we provide the clinical, biochemical and genetic investigation for unrelated three nuclear families presenting an autosomal form of Spino-Cerebellar Ataxia due to novel mutations in the ADCK3 gene. Using next generation sequence technology we identified a homozygous Gln343Ter mutation in one family with severe, early onset of the disease and compound heterozygous mutations of Gln343Ter and Ser608Phe in two other families with variable manifestations. Biochemical investigation in fibroblasts showed decreased activity of the CoQ dependent mitochondrial respiratory chain enzyme succinate cytochrome c reductase (complex II + III). Exogenous CoQ slightly improved enzymatic activity, ATP production and decreased oxygen free radicals in some of the patient's cells. Our results are presented in comparison to previously reported mutations and expanding the clinical, molecular and biochemical spectrum of ADCK3 related CoQ10 deficiencies.

Ataxia with novel compound heterozygous PEX10 mutations and a literature review of PEX10-related peroxisome biogenesis disorders

ObjectivesTo describe the clinical and genetic features of a Chinese peroxisome biogenesis disorder 6B patient with PEX10 mutations and review PEX10–related peroxisomal disorders. Patients and methodsThe proband is a 7-year-old boy with mild mental retardation and gait instability, intention tremor and nystagmus. An extensive clinical and laboratory evaluation including molecular genetic studies was performed. Genomic DNA was extracted from peripheral blood using the standardized phenol/chloroform extraction method, and the coding region of the PEX10 gene was sequenced in three family members. ResultsCerebral MRI showed cerebellar atrophy. Magnetic resonance spectroscopy revealed a decreased N-acetyl aspartate peak in the cerebellum. Nerve conduction velocity examination found prolonged motor and sensory nerve potential latencies (proximal obvious), decreased potential amplitude, and slow nerve conduction velocity. Routine blood tests and biochemistries were abnormal. The PEX10 gene test showed compound heterozygous mutations (c.209 G > A, p. G70E and c.830 T > C, p. L277 P). The mutation c.830 T > C, p. L277 P has been previously reported, whereas c.209 G > A, p. G70E is novel. ConclusionWe identified an ataxia case of peroxisome biogenesis disorder 6B caused by novel compound heterozygous mutations of the PEX10 gene. Peroxisome biogenesis disorders should be considered in the differential diagnosis of autosomal recessive ataxia, especially cases with early onset.

Diagnostic algorithm for autosomal recessive ataxia

To develop a complex algorithm for autosomal recessive ataxia (ARA) diagnosis applicable for Russian patients with degenerative ataxias. 48 patients with of presumably degenerative ataxias were examined. Clinical evaluation was performed with the use of the SARA and ICARS scales (for ataxia) and MoCA (cognitive functions), and a set of laboratory tests was carried out, including electromyography, brain MRI, and DNA analysis of mutations responsible for Friedreich's disease and spinocerebellar ataxias (SCAs) types 1, 2, 3, 6 and 17. 28 patients underwent mutation screening using a multigenic MPS panel. 8 patients (16.7%) with non-hereditary causes of ataxia were identified: cerebellar alcoholic degeneration (n = 6) and multiple system atrophy of cerebellar type (n = 2); 3 patients (6.3%) with genetic ataxias were identified using routine DNA tests, such as with SCA type 1, 2 and 17, and 9 (18.8%) patients with Friedreich's disease. The MPS panel enabled molecular diagnosis of ARA in 8 patients (28.6%): ataxia-telangiectasia (n = 2), SANDO syndrome (n = 2), ataxia with oculomotor apraxia type 2 (n = 1), SCAR10 (n = 1), SCAR16 (n = 1), and atypical form of neuroaxonal dystrophy (n = 1). The diagnosis was not established in 20 patients. We have proposed an appropriate algorithm for degenerative ataxia diagnosis which is recommended to be used when examining patients with sporadic and autosomal recessive cases of the disorders with dyscoordination of movements.

Targeting Tyrosyl-DNA phosphodiesterase I to enhance toxicity of phosphodiester linked DNA-adducts.

Our genomic DNA is under constant assault from endogenous and exogenous sources, which needs to be resolved to maintain cellular homeostasis. The eukaryotic DNA repair enzyme Tyrosyl-DNA phosphodiesterase I (Tdp1) catalyzes the hydrolysis of phosphodiester bonds that covalently link adducts to DNA-ends. Tdp1 utilizes two catalytic histidines to resolve a growing list of DNA-adducts. These DNA-adducts can be divided into two groups: small adducts, including oxidized nucleotides, RNA, and non-canonical nucleoside analogs, and large adducts, such as (drug-stabilized) topoisomerase- DNA covalent complexes or failed Schiff base reactions as occur between PARP1 and DNA. Many Tdp1 substrates are generated by chemotherapeutics linking Tdp1 to cancer drug resistance, making a compelling argument to develop small molecules that target Tdp1 as potential novel therapeutic agents. Tdp1’s unique catalytic cycle, which is centered on the formation of Tdp1-DNA covalent reaction intermediate, allows for two principally different targeting strategies: (1) catalytic inhibition of Tdp1 catalysis to prevent Tdp1-mediated repair of DNA-adducts that enhances the effectivity of chemotherapeutics; and (2) poisoning of Tdp1 by stabilization of the Tdp1- DNA covalent reaction intermediate, which would increase the half-life of a potentially toxic DNA-adduct by preventing its resolution, analogous to topoisomerase targeted poisons such as topotecan or etoposide. The catalytic Tdp1 mutant that forms the molecular basis of the autosomal recessive neurodegenerative disease spinocerebellar ataxia with axonal neuropathy best illustrates this concept; however, no small molecules have been reported for this strategy. Herein, we concisely discuss the development of Tdp1 catalytic inhibitors and their results.

Identifying SYNE1 Ataxia With Novel Mutations in a Chinese Population.

Objective: Variants in SYNE1 have been widely reported in ataxia patients in Europe, with highly variable clinical phenotype. Until now, no mutation of SYNE1 ataxia has been reported among the Chinese population. Our aim was to screen for SYNE1 ataxia patients in China and extend the clinicogenetic spectrum.Methods: Variants in SYNE1 were detected by high-throughput sequencing on a cohort of 126 unrelated index patients with unexplained autosomal recessive or sporadic ataxia. Pathogenicity assessments of SYNE1 variants were interpreted according to the ACMG guidelines. Potential pathogenic variants were confirmed by Sanger sequencing. Clinical assessments were conducted by two experienced neurologists.Results: Two Chinese families with variable ataxia syndrome were identified (accounting for 1.6%; 2/126), separately caused by the novel homozygous SYNE1 mutation (NM_033071.3: c.21568C>T, p.Arg7190Ter), and compound heterozygous SYNE1 mutation (NM_033071.3: c.18684G>A, p.Trp6228Ter; c.17944C>T, p.Arg5982Ter), characterized by motor neuron impairment, mental retardation and arthrogryposis.Conclusions: SYNE1 ataxia exists in the Chinese population, as a rare form of autosomal recessive ataxia, with a complex phenotype. Our findings expanded the ethnic, phenotypic and genetic diversity of SYNE1 ataxia.

CAPN1 mutations: Expanding the CAPN1-related phenotype: From hereditary spastic paraparesis to spastic ataxia

Aims and objectiveTo characterize the phenotype of CAPN1 (SPG76) mutations in patients diagnosed with hereditary spastic paraplegia (HSP). BackgroundThe CAPN1 gene, located on chromosome 11q13.1, is a protein-coding gene involved in neuronal plasticity, migration, microtubular regulation and cerebellar development. Several families with CAPN1 mutations have recently been reported to present with autosomal recessive (AR) HSP and/or ataxia. MethodPatients with HSP were identified through neurological and genetic clinics with detailed phenotyping. Whole exome sequencing revealed novel pathogenic CAPN1 mutations in four patients from 3 families. ResultsAffected families were of Turkish, Japanese, and Punjabi descent and all were consanguineous. Onset of spastic paraplegia in the four patients was between 20 and 37 years. Two also had mild ataxia. Three different novel, homozygous mutations in CAPN1 were found: c.2118+1G > T, c.397C > T, c.843+1G > C. The patient with the earliest onset also manifested profound muscle weakness, likely related to a second homozygous mutation in DYSF (dysferlinopathy). ConclusionsThe phenotype of AR CAPN1 mutations appears to be spastic paraplegia with or without ataxia; onset is most commonly in adulthood. Eye movement abnormalities, skeletal defects, peripheral neuropathy and amyotrophy can sometimes be seen. Occasionally, patients can present with ataxia, illustrating the genotypic and phenotypic overlap between HSP and spastic ataxia. With the advent of exome sequencing, mutations in more than one gene can be identified, which may contribute to the phenotypic variation, even within a family.

Past and Present of Eye Movement Abnormalities in Ataxia-Telangiectasia.

Ataxia-telangiectasia is the second most common autosomal recessive hereditary ataxia, with an estimated incidence of 1 in 100,000 births. Besides ataxia and ocular telangiectasias, eye movement abnormalities have long been associated with this disorder and is frequently present in almost all patients. A handful of studies have described the phenomenology of ocular motor deficits in ataxia-telangiectasia. Contemporary literature linked their physiology to cerebellar dysfunction and secondary abnormalities at the level of brainstem. These studies, while providing a proof of concept of ocular motor physiology in disease, i.e., ataxia-telangiectasia, also advanced our understanding of how the cerebellum works. Here, we will summarize the clinical abnormalities seen with ataxia-telangiectasia in each subtype of eye movements and subsequently describe the underlying pathophysiology. Finally, we will review how these deficits are linked to abnormal cerebellar function and how it allows better understanding of the cerebellar physiology.

Developmental and neurodegenerative damage in Friedreich's ataxia.

Friedreich's ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide. It is characterized by early onset, sensory abnormalities and slowly progressive ataxia. All magnetic resonance imaging (MRI)-based studies have focused on the evaluation of adult patients. Therefore, we designed a cross-sectional multimodal MRI-based study to investigate the anatomical substrates involved in the early stages of FRDA. We enrolled 37 patients (12 children) and 38 controls. All subjects underwent MRI in a 3T device to assess gray and white matter. We used measures from FreeSurfer and CERES to evaluate the cerebral and cerebellar cortices. The T1 multiatlas assessed deep gray matter. The diffusion tensor imaging multiatlas was used to investigate microstructural abnormalities in brain white matter and SpineSeg was used to assess the cervical spinal cord. All analyses were corrected for multiple comparisons. Comparison with age-matched controls showed that pediatric patients have spinal cord, inferior cerebellar peduncle and red nucleus damage. In contrast, adult patients showed more widespread white matter damage than pediatric patients. With regard to gray matter, we found cortical thinning at the left central sulcus and volumetric reduction in the thalami and hippocampi only in adult patients. Finally, values of fractional anisotropy in adult patients and radial diffusivity in pediatric patients from the inferior cerebellar peduncle correlated with disease duration and ataxia severity, respectively. Structural damage in FRDA begins in the spinal cord and inferior cerebellar peduncle as well as the red nucleus, and progresses to cerebral areas in adulthood. These results shed some light on the early stages of FRDA and highlight potential neuroimaging markers for therapeutic trials.

ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype.

Autosomal recessive cerebellar ataxia type 3 (ARCA3) is a rare inherited disorder caused by mutations in the ANO10 gene. The disease is characterized by slowly progressive spastic ataxia variably associated with motor neuron involvement, epilepsy, and cognitive decline. We performed mutational screening in 80 patients with sporadic or autosomal recessive adult-onset ataxia. We identified 11 ANO10 gene variants in 10 patients from 8 families (10%): 4 mutations were previously described and 7 were novel. Age at onset ranged between 27 and 53years. All patients presented ataxia, pyramidal signs and cerebellar atrophy at brain MRI. Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10). Six patients, with normal MMSE score, failed several neuropsychological tests rating executive functions. Three patients had giant somatosensory evoked potentials and epileptic spikes in EEG without clinical evidence of seizures. Our observational study indicates a high frequency of ARCA3 disease in sporadic patients with adult-onset cerebellar ataxia. We extended the ANO10 mutational spectrum with the identification of novel gene variants, and further defined the clinical, cognitive, and neurophysiological features in a new cohort of patients. These findings may contribute to the refinement of the complex ARCA3 phenotype and be valuable in clinical management and natural history studies.

Plasma Markers of Neurodegeneration Are Raised in Friedreich's Ataxia.

Background: Friedreich’s ataxia (FRDA) is the most common autosomal recessive ataxia. Disease-modifying treatments are not available yet; however, several compounds are currently under investigation. As a result, there is a growing need for the identification of robust and easily accessible biomarkers for the monitoring of disease activity and therapeutic efficacy. The simultaneous measurement of multiple brain-derived proteins could represent a time- and cost-efficient approach for biomarker investigation in pathologically complex neurodegenerative diseases like FRDA.Objectives: To investigate the role of plasma neurofilament-light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (t-tau) and ubiquitin C-terminal hydrolase L1(UCHL1) as biomarkers in FRDA. Additionally, NfL measurements derived from the novel multiplex assay were compared to those from an established NfL singleplex assay.Methods: In this study, an ultrasensitive Single molecule array (Simoa) 4-plex assay was used for the measurement of plasma NfL, GFAP, t-tau, and UCHL1 in 33 FRDA patients and 13 age-matched controls. Differences in biomarker concentrations between these groups were computed and associations with genetic and disease related parameters investigated. Additionally, the agreement between NfL measurements derived from the 4-Plex and an established Simoa NfL singleplex assay was assessed.Results: Mean plasma NfL, GFAP and UCHL1 levels were significantly higher in FRDA patients than in controls (NfL: p < 0.001; GFAP: p = 0.006, and UCHL1: p = 0.020). Conversely, there was no significant difference in concentrations of t-tau in the patient and control group (p = 0.236). None of the proteins correlated with the GAA repeat length or the employed measures of disease severity. The individual NfL values derived from the two assays showed a strong concordance (rc = 0.93). Although the mean difference of 1.29 pg/mL differed significantly from 0 (p = 0.006), regression analysis did not indicate the presence of a proportional bias.Conclusion: This is the first study demonstrating that NfL, GFAP, and UCHL1 levels are raised in FRDA, potentially reflecting ongoing neuronal degeneration and glial activation. Further studies are required to determine their role as marker for disease activity and progression. Furthermore, the novel 4-plex assay appears to be a valid tool to simultaneously measure brain-derived proteins at extremely low concentrations in the peripheral circulation.

Ataxia telangiectasia alters the ApoB and reelin pathway.

Autosomal recessive ataxia telangiectasia (A-T) is characterized by radiosensitivity, immunodeficiency, and cerebellar neurodegeneration. A-T is caused by inactivating mutations in the ataxia telangiectasiamutated (ATM) gene, a serine-threonine protein kinase involved in DNA damage response and excitatory neurotransmission. The selective vulnerability of cerebellar Purkinje neurons (PN) to A-T is not well understood. Employing global proteomic profiling of cerebrospinal fluid from patients at ages around 15years, we detected reduced calbindin, reelin, cerebellin-1, cerebellin-3, protocadherin fat 2, sempahorin 7A, and increased apolipoprotein B and J peptides. Bioinformatic enrichment was observed for pathways of lipoproteins, endocytosis, extracellular matrix receptor interaction, peptidase activity, adhesion, calcium binding, and complement immunity. This seemed important since secretion of reelin from glutamatergic afferent axons is crucial for PN lipoprotein receptor endocytosis and lipid signaling. Reelin expression is downregulated by irradiation and reelin/ApoB mutations are known causes of ataxia. Validation efforts in 2-month-old Atm-/- mice before onset of motor deficits confirmed cerebellar transcript reductions for reelin receptors Apoer2/Vldlr with increases for their ligands Apoe/Apoh and cholesterol 24-hydroxylase Cyp46a1. Concomitant dysregulations were found for Vglut2/Sema7a as climbing fiber markers, glutamate receptors like Grin2b, and calcium homeostasis factors (Atp2b2, Calb1, Itpr1), while factors involved in DNA damage, oxidative stress, neuroinflammation, and cell adhesion were normal at this stage. Quantitative immunoblots confirmed ApoB and ApoJ increases and VLDLR reduction in cerebellar tissue at the age of 2months. These findings show that ApoB excess and reelin signaling deficits reflect the neurodegeneration in A-T in a sensitive and specific way. As extracellular factors, apolipoproteins and their cargo such as vitamin E may be useful for neuroprotective interventions.

SYNE1-related autosomal recessive cerebellar ataxia, congenital cerebellar hypoplasia, and cognitive impairment.

The spectrin repeat-containing nuclear envelope protein 1 (SYNE1) gene encodes a family of spectrin structural proteins that are associated with anchoring the plasma membrane to the actin cytoskeleton. SYNE1-related disease is most commonly reported in autosomal recessive spinocerebellar ataxia 8, which demonstrates variable age of onset with a median of 30 years of age. However pathogenic mutations in SYNE1 are also causative of arthrogryposis multiplex congenital, a severe congenital neuromuscular condition. Here in we report monozygous twins with childhood onset ataxia, cerebellar hypoplasia, dysarthria, and cognitive impairment sharing two novel heterozygous mutations in the SYNE1 gene. Our family may expand the clinical phenotype associated with SYNE1-related disease and offers possible genotype-phenotype correlations of a rare continuum of clinical disease phenotypes from neonatal to adult onset.

Keys to overcoming the challenge of diagnosing autosomal recessive spinocerebellar ataxia

IntroductionAutosomal recessive spinocerebellar ataxia refers to a large group of diseases affecting the cerebellum and/or its connections, although they may also involve other regions of the nervous system. These diseases are accompanied by a wide range of systemic manifestations (cardiopathies, endocrinopathies, skeletal deformities, and skin abnormalities). DevelopmentThis study reviews current knowledge of the most common forms of autosomal recessive spinocerebellar ataxia in order to provide tips that may facilitate diagnosis. ConclusionsA thorough assessment of clinical phenotype (pure cerebellar or cerebellar-plus syndrome, with or without systemic manifestations), laboratory tests (vitamin E, acanthocytosis, albumin, cholesterol, phytanic acid, lactic acid, creatine kinase, cholestanol, coenzyme Q10, alpha-fetoprotein, copper, ceruloplasmin, chitotriosidase), nerve conduction studies (presence and type of neuropathy), and an magnetic resonance imaging study (presence of cerebellar atrophy, presence and location of signal alterations) may help establish a suspected diagnosis, which should be confirmed by detecting the underlying genetic mutation. A positive genetic test result is necessary to determine prognosis and provide adequate genetic counselling, and will also permit appropriate treatment of some entities (abetalipoproteinaemia, ataxia with vitamin E deficiency, Refsum disease, cerebrotendinous xanthomatosis, Niemann-Pick disease type C, Wilson disease). Without a genetic diagnosis, conducting basic research and therapeutic trials will not be possible.

Identifying SYNE1 ataxia and extending the mutational spectrum in Korea

IntroductionRecent advances in next generation sequencing technologies have uncovered the genetic background of various diseases. The mutations in the SYNE1 gene was previously identified as a potential cause of pure cerebellar ataxia. Although autosomal recessive ataxias are slightly more frequent than autosomal dominant forms worldwide, autosomal recessive forms are extremely rare in Korea. In this study, we aimed to identify SYNE1-associated ataxia by whole exome sequencing in a Korean sample, and to review the prevalence of SYNE1 in non-French-Canadians. MethodsPatients with suspected cerebellar ataxia who visited movement disorders clinic from March 2014 to December 2017 were clinically screened. After excluding cases with acquired causes and common genetic causes in Korea, including spinocerebellar ataxia and dentatorubral-pallidoluysian atrophy, 63 undiagnosed subjects were screened for SYNE1 mutations by next generation sequencing methods. ResultsWe identified four novel mutations (one splicing, one truncating, and two missense mutations) distributed throughout the SYNE1 gene in two patients. The phenotype was mainly pure cerebellar ataxia in both cases. However, axonal neuropathy, mild frontal dysfunction, and autonomic dysfunction were also revealed. The age of disease onset was relatively late and the disease course was only mildly progressive. ConclusionOur results indicate that SYNE1 mutations are not an uncommon cause of recessive ataxia with additional clinical features in the Korean population. The results of this study should alert neurologists to request SYNE1 testing to aid the diagnosis of undetermined adult-onset ataxia in Korean patients.

WWOX-associated encephalopathies: identification of the phenotypic spectrum and the resulting genotype-phenotype correlation

Epileptic encephalopathies are a group of disorders in which epileptiform abnormalities cause progressive deterioration in cerebral function. Genetic causes have been described in several of the epileptic encephalopathies, and many previously unknown genes have been identified. WW domain-containing oxidoreductase (WWOX) has recently been implicated in autosomal recessive spinocerebellar ataxia type 12 (SCAR12) and severe early-onset epileptic encephalopathy. With whole-exome sequencing, we identified a homozygous WWOX missense mutation, p.Leu239Arg, in a girl from a consanguineous family with psychomotor developmental delay, acquired microcephaly, and epileptic seizures. WWOX-related epileptic encephalopathy is a rare condition but it should be considered in cases having early epileptic spasms and parental consanguinity.

P14. Sodium magnetic resonance imaging in Friedreich ataxia – A preliminary study

Friedreich ataxia (FRDA) is the most common autosomal recessive inherited ataxia, mainly caused by a GAA trinucleotide repeat expansion in the FRDA gene encoding the protein frataxin (Bradley et al., 2000). Magnetic resonance imaging (MRI) has successfully been used to detect abnormalities in the brainstem, cerebellum and cortex in FRDA ([Franca et al., 2009], [Dogan et al., 2016]). Here, we used in vivo sodium MRI to investigate cerebral metabolic changes in FRDA (Reetz et al., 2012). Can sodium MRI provide a deeper insight into the metabolic pathophysiology in FRDA? Is the total sodium concentration (TSC) in brain tissue of FRDA patients higher than of controls?. We studied 11 FRDA patients (6 females; mean age = 36.36 [12.55]) and 8 healthy controls (7 females; mean age = 32.88 [8.92]). We estimated the TSC in the cerebellar white matter (left and right CWM) and in the brainstem from sodium MRI acquired on a 3 Tesla whole-body MR scanner (PRISMA, Siemens Medical Systems, Erlangen). Total scan time was 20 min, isotropic resolution 4 mm3. Clinically, we assessed the major symptom ataxia with the Scale for the Assessment and Rating of Ataxia (SARA) (Reetz et al., 2016). One-tailed Student’s t-test was used for mean TSC between groups. Pearson correlation was conducted between mean TSC and SARA scores, age, age of onset, disease duration as well as GAA repeats of both alleles in FRDA patients. In FRDA patients we found ahigher TSC in the left CWM (mean [M] = 45.77, standard error [SE] = .71) and in the brainstem (M = 46.76, SE = 1.03) in comparison to controls (left CWM [M = 43.40, SE = .75; t[17] = −2.27], brainstem [M = 43.70, SE = .97; t[17] = −2.09]; both p<.05). In the right CWM, there were marginally significant higher TSC levels in patients (M = 45.05, SE = .81) than in controls (M = 43.55, SE = .59; t[16.68] = −1.49, p<.10). A positive relationship was found between SARA scores and TSC in all three brain areas (left CWM [r = .50,p<.10], right CWM [r = .66, p<.05], brainstem [r = .65, p<.05]). Remaining correlations gained no significance (p>.05). The increase of TSC in cerebellum and brainstem in FRDA patients suggests the diagnostic potential of in vivo sodium MRI to differentiate between patients and controls. Moreover, this was related to more severe ataxia, as assessed by the SARA. These preliminary results support our hypothesis that sodium MRI may be a new imaging marker that could shed new insights into the metabolic pathophysiological mechanisms of FRDA.

Current and Promising Therapies in Autosomal Recessive Ataxias.

Ataxia is clinically characterized by unsteady gait and imbalance. Cerebellar disorders may arise from many causes such as metabolic diseases, stroke or genetic mutations. The genetic causes are classified by mode of inheritance and include autosomal dominant, X-linked and autosomal recessive ataxias. Many years have passed since the description of the Friedreich's ataxia, the most common autosomal recessive ataxia, and mutations in many other genes have now been described. The genetic mutations mostly result in the accumulation of toxic metabolites which causes Purkinje neuron lost and eventual cerebellar dysfunction. Unfortunately, the recessive ataxias remain a poorly known group of diseases and most of them are yet untreatable. The aim of this review is to provide a comprehensive clinical profile and to review the currently available therapies. We overview the physiopathology, neurological features and diagnostic approach of the common recessive ataxias. The emphasis is also made on potential drugs currently or soon-to-be in clinical trials. For instance, promising gene therapies raise the possibility of treating differently Friedreich's ataxia, Ataxia-telangiectasia, Wilson's disease and Niemann-Pick disease in the next few years.

Multimodal neuroimaging analysis in patients with SYNE1 Ataxia

BackgroundThe gene SYNE1 is highly expressed in the cerebellum and its dysfunction is related to an autosomal recessive ataxia (SYNE1-ataxia). The disease was firstly considered a pure cerebellar ataxia however, recent studies have described a broader clinical presentation, including motor neuron disease symptoms. ObjectivesTo investigate cerebellar and potential extra-cerebellar changes in SYNE1-ataxia using multimodal neuroimaging analyses. MethodsSix patients completed clinical and imaging exams, and were compared to age-gender-matched healthy controls. Gray matter was analyzed using FreeSurfer and CERES for brain and cerebellum, respectively. White matter was analyzed with DTI-TBSS while we used SpineSeg for spinal cord analysis. ResultsWe found significantly reduced cortical thickness (p < 0.05, FDR-corrected) in primary and association cortices, and volume reduction in subcortical structures, brainstem and cerebellum. White matter was found disrupted in both brain and cerebellum (p < 0.05, FWE-corrected). These results are consistent with the expression of the SYNE1 mRNA and its encoded protein in the brain. We failed to demonstrate spinal cord changes. ConclusionsSYNE1-ataxia is, therefore, a relatively common cause of recessive ataxia characterized by complex multisystemic neurostructural changes consistent with the phenotypic heterogeneity and neuroimaging configures a potential marker of the disease.