Overwhelming genetic heterogeneity and exhausting molecular diagnostic process in chronic and progressive ataxias: facing it up with an algorithm, a gene, a panel at a time.

Ataxias are one of the most frequent complaints in Neurogenetics units worldwide. Currently, more than 50 subtypes of spinocerebellar ataxias and more than 60 recessive ataxias are recognized. We conducted an 11-year prospective, observational, analytical study in order to estimate the frequency of pediatric and adult genetic ataxias in Argentina, to describe the phenotypes of this cohort and evaluate the diagnostic yield of the algorithm used in our unit. We included 334 ataxic patients. Our diagnostic approach was successful in one-third of the cohort. A final molecular diagnosis was reached in 113 subjects. This rate is significantly higher in the subgroup of patients with a positive family history, where the diagnostic yield increased to 55%. The most prevalent dominant and recessive ataxias in Argentina were SCA-2 (36% of dominant ataxias) and FA (62% of recessive ataxias), respectively. Next generation sequencing-based assays were diagnostic in the 65% of the patients requiring these tests. These results provide relevant epidemiological information, bringing a comprehensive knowledge of the most prevalent subtypes of genetic ataxias and their phenotypes in our territory and laying the groundwork for rationally implementing genetic diagnostic programs for these disorders in our country.

The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force.

There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.

Classifications of neurogenetic diseases: An increasingly complex problem.

Neurodegenerative disorders represent a wide group of diseases affecting the central and/or peripheral nervous system. Many of these disorders were described in the 19th century, but our genetic knowledge of them is recent (over the past 25 years). However, the continual discovery of disease-causing gene mutations has led to difficulties in the classification of these diseases. For this reason, our present proposals for updating and simplifying the classification of some of these conditions (Charcot-Marie-Tooth diseases, distal hereditary motor neuropathies, hereditary sensory and autonomic neuropathies, hereditary spastic ataxias, hereditary spastic paraplegias and hereditary spastic ataxias) are expounded here.

Novel mutations in typical and atypical genetic loci through exome sequencing in autosomal recessive cerebellar ataxia families.

Nearly a thousand mutations mapping to 60 different loci have been identified in cerebellar ataxias. However, almost 50% of the cases remain genetically uncharacterized and there is a difference in prevalence as well as in the phenotypic spectrum of ataxia among various geographical regions. This poses a challenge for setting up a genetic panel for screening ataxia. In our ataxic cohort of 1014 families, 61% are genetically uncharacterized (UC). We investigated the potential of whole exome sequencing in conjunction with homozygosity mapping (HM) to delineate the genetic defects in three uncharacterized families with recessive inheritance each manifesting some unusual phenotype: (i) infantile onset ataxia with hearing loss (IOAH), (ii) Juvenile onset cerebellar ataxia with seizures (JCS) and (iii) Friedreich ataxia-like (FA-like). We identified a novel missense mutation in c10orf2 in the family with IOAH, compound heterozygous mutations in CLN6 in the family with JCS and a homozygous frame-shift mutation in SACS in the FA-like patient. Phenotypes observed in our families were concordant with reported phenotypes of known mutations in the same genes thus obviating the need for functional validation. Our study revealed novel variations in three genes, c10orf2, CLN6, and SACS, that have so far not been reported in India. This study also demonstrates the utility of whole exome screening in clinics for early diagnosis.

[Have centers of rare neurological diseases changed their practices and management of the hereditary cerebellar ataxias?]. / Les centres maladies rares en neurologie ont-ils changé les pratiques et la prise en charge dans les ataxies cérebelleuses héréditaires?

The classification and management of hereditary cerebellar ataxias have been considerably changed by advances made in the field of genetics. Given the numerous genes implicated in the disorders, genetic analysis, which alone can confirm the diagnosis, needs to be based on phenotypically precise studies. Diagnostic algorithms including both recessive and dominant forms of ataxia have been proposed. The range of disease effects has been further expanded in the light of evidence of ataxias associated with permutations of the Fragile X gene, and ataxias linked to mutations of the nuclear genes coding for structural proteins of mitochondrial DNA. In the field of therapeutics, several studies are currently ongoing for Friedreich's ataxia.

Recent advances in the genetics of cerebellar ataxias.

The hereditary cerebellar ataxias are a clinically and genetically heterogeneous group of disorders that primarily affect the cerebellum; often there are additional features such as neuropathy, cognitive decline, or maculopathy that help define the clinical subtype of ataxia. They are commonly classified according to their mode of inheritance into autosomal dominant, autosomal recessive, X-linked, and mitochondrial forms. Great advances have been made in understanding the genetics of cerebellar ataxias in the last 15 years. At least 36 different forms of ADCA are known, 20 autosomal-recessive, two X-linked, and several forms of ataxia associated with mitochondrial defects are known to date. However, in about 40 % of suspected genetically determined ataxia cases, the underlying genetic defect remains undetermined. Although the majority of disease genes have been found in the last two decades, over the last 2 years the genetics has undergone a methodological revolution. New DNA sequencing technologies are enabling us to investigate the whole or large targeted proportions of the genome in a rapid, affordable, and comprehensive way. Exome and targeted sequencing has recently identified four new genes causing ataxia: TGM6, ANO10, SYT14, and rundataxin. This approach is likely to continue to discover new ataxia genes and make screening of existing genes more effective. Translating the genetic findings into isolated and overlapping disease pathways will help stratify patient groups and identify therapeutic targets for ataxia that have so far remained undiscovered.

[Recent advance in genetic study of hereditary autosomal recessive cerebellar ataxia].

Autosomal recessive cerebellar ataxias (ARCA) are a highly heterogeneous group of rare neurodegenerative diseases affecting both central and peripheral nervous systems. Based on pathological mechanisms, five major types of ARCA may be distinguished, which include mitochondrial ataxia, metabolic disorder, DNA repair defect ataxia, congenital ataxias and degenerative ataxia. This review summarizes clinical features, molecular genetics and recent advances in DNA sequencing of common types of ARCA.

Comparison of cerebellar ataxias: A three-year prospective longitudinal assessment.

We quantitatively investigated the clinical severity and progression of diseases with ataxia, as measured with the Scale for the Assessment and Rating of Ataxia, and examined the potential application of the Scale for the Assessment and Rating of Ataxia for future therapeutic trials. Severity of ataxia was assessed in 238 patients with spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, spinocerebellar ataxia type 6, spinocerebellar ataxia type 17, multiple system atrophy-cerebellar variant, or Gerstman-Sträussler-Scheinker disease. Among them, 119 (50%) were longitudinally examined three to seven times, in a period of 8 to 38 months, resulting in a total set of 535 assessments. The differences between spinocerebellar ataxia and multiple system atrophy-cerebellar variant were ascertained cross-sectionally and longitudinally. Gerstman-Sträussler-Scheinker disease had the fastest progression, followed by multiple system atrophy-cerebellar variant, spinocerebellar ataxia type 17, spinocerebellar ataxia type 3, spinocerebellar ataxia type 2, and spinocerebellar ataxia type 6. Patients with multiple system atrophy-cerebellar variant had a faster progression in gait, sitting, speech, and total score than patients with spinocerebellar ataxias. For a randomized, case-control trial, a sample size of 47 for spinocerebellar ataxia and 85 for multiple system atrophy-cerebellar variant in the treatment or placebo arms would have a sufficient statistical power to demonstrate the efficacy of a new therapy that would retard ataxia progression by 1 point per year as measured by the Scale for the Assessment and Rating of Ataxia. The results will have a significant impact on the planning and implementation of future therapeutic trials of spinocerebellar ataxia and multiple system atrophy-cerebellar variant.

Safety and Efficacy of Acetyl-DL-Leucine in Certain Types of Cerebellar Ataxia: The ALCAT Randomized Clinical Crossover Trial.

Importance: Cerebellar ataxia is a neurodegenerative disease impairing motor function characterized by ataxia of stance, gait, speech, and fine motor disturbances. Objective: To investigate the efficacy, safety, and tolerability of the modified essential amino acid acetyl-DL-leucine in treating patients who have cerebellar ataxia. Design, Setting, and Participants: The Acetyl-DL-leucine on Cerebellar Ataxia (ALCAT) trial was an investigator-initiated, multicenter, double-blind, randomized, placebo-controlled, clinical crossover trial. The study was conducted at 7 university hospitals in Germany and Austria between January 25, 2016, and February 17, 2017. Patients were aged at least 18 years and diagnosed with cerebellar ataxia of hereditary (suspected or genetically confirmed) or nonhereditary or unknown type presenting with a total score of at least 3 points on the Scale for the Assessment and Rating of Ataxia (SARA). Statistical analysis was performed from April 2018 to June 2018 and January 2020 to March 2020. Interventions: Patients were randomly assigned (1:1) to receive acetyl-DL-leucine orally (5 g per day after 2 weeks up-titration) followed by a matched placebo, each for 6 weeks, separated by a 4-week washout, or vice versa. The randomization was done via a web-based, permuted block-wise randomization list (block size, 2) that was stratified by disease subtype (hereditary vs nonhereditary or unknown) and site. Main Outcomes and Measures: Primary efficacy outcome was the absolute change of SARA total score from (period-dependent) baseline to week 6. Results: Among 108 patients who were randomly assigned to sequence groups (54 patients each), 55 (50.9%) were female; the mean (SD) age was 54.8 (14.4) years; and the mean (SD) SARA total score was 13.33 (5.57) points. The full analysis set included 105 patients (80 patients with hereditary, 25 with nonhereditary or unknown cerebellar ataxia). There was no evidence of a difference in the mean absolute change from baseline to week 6 in SARA total scores between both treatments (mean treatment difference: 0.23 points [95% CI, -0.40 to 0.85 points]). Conclusions and Relevance: In this large multicenter, double-blind, randomized, placebo-controlled clinical crossover trial, acetyl-DL-leucine in the investigated dosage and treatment duration was not superior to placebo for the symptomatic treatment of certain types of ataxia. The drug was well tolerated; and ALCAT yielded valuable information about the duration of treatment periods and the role of placebo response in cerebellar ataxia. These findings suggest that further symptom-oriented trials are needed for evaluating the long-term effects of acetyl-DL-leucine for well-defined subgroups of cerebellar ataxia. Trial Registration: EudraCT 2015-000460-34.

Autosomal dominant cerebellar ataxia: frequency analysis and clinical characterization of 45 families from Portugal.

BACKGROUND AND PURPOSE: The relative frequency of the different autosomal dominant cerebellar ataxia (ADCA) varies widely amongst different geographic locations. Here we describe a series of 45 ADCA families from Portugal. METHODS: Patients with progressive cerebellar dysfunction of autosomal dominant transmission underwent a clinical examination protocol and genetic testing for spinocerebellar ataxia (SCA)1 to Machado-Joseph disease (MJD)/SCA3, SCA6, SCA7, SCA10, SCA12, SCA17 and dentatorubral-pallidoluysian atrophy (DRPLA). We registered the clinical characteristics and frequency of each type of ataxia. RESULTS: MJD/SCA3 was the most frequent ADCA (26 families, 57.8% of all families), followed by DRPLA (5 families, 11.2%), SCA7 (2 families, 4.4%), SCA2 and SCA1 (1 family each, 2.2% each); 10 families (22.2%) had no molecular diagnosis. SCA1 and SCA7 patients had African ancestry. DRPLA patients had Portuguese ancestry and were characterized by prominent anticipation and a variable combination of epilepsy, extra-pyramidal symptoms and dementia. Ophtalmoparesis, slow saccades and retinopathy were most distinctive of SCA3, SCA2 and SCA7 cases, respectively. CONCLUSIONS: MJD/SCA3 was the most common ADCA in this group of families. The high frequency of DRPLA and presence of SCA1 and SCA7 cases was unexpected. The presence of these rarer ADCA types probably reflects migration phenomena, posing a challenge for differential diagnosis.

Cerebellar ataxias.

PURPOSE OF REVIEW: The term 'cerebellar ataxias' encompasses the various cerebellar disorders encountered during daily practice. Patients exhibit a cerebellar syndrome and can also present with pigmentary retinopathy, extrapyramidal movement disorders, pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioural symptoms), and peripheral neuropathy. The clinical diagnosis of subtypes of ataxias is complicated by the salient overlap of the phenotypes between genetic subtypes. The identification of the causative mutations of many hereditary ataxias and the development of relevant animal models bring hope for effective therapies in neurodegenerative ataxias. RECENT FINDINGS: We describe the current classification of cerebellar ataxias and underline the recent discoveries in molecular pathogenesis. Cerebellar disorders can be divided into sporadic forms and inherited diseases. Inherited ataxias include autosomal recessive cerebellar ataxias, autosomal dominant cerebellar ataxias/spinocerebellar ataxia) and episodic ataxias, and X-linked ataxias. From a motor control point of view, the leading theories of ataxia are based on neural representations or 'internal models' to emulate fundamental natural processes such as body motion. SUMMARY: Recent molecular advances have direct implications for research and daily practice. We provide a framework for the diagnosis of ataxias. For the first time, the therapeutic agents under investigation are targeted to deleterious pathways.

Severity and progression rate of cerebellar ataxia in 16q-linked autosomal dominant cerebellar ataxia (16q-ADCA) in the endemic Nagano Area of Japan.

16q22.1-linked autosomal dominant cerebellar ataxia (16q-ADCA) is a recently defined subtype of ADCA identified by a disease-specific C/T substitution in the 5' untranslated region of the puratrophin-1 gene. In Nagano, the central mountainous district of the main island of Japan, 16q-ADCA and spinocerebellar ataxia type 6 (SCA6) are the most and second most prevalent subtypes of ADCA, respectively. Both subtypes are classified into Harding's ADCA III, but little attention has been given to the differences in the severity and progression rate of cerebellar ataxia between 16q-ADCA and SCA6. We investigated the clinical severity and progression rate of cerebellar ataxia of 16q-ADCA patients using international cooperative ataxia rating scale and scale for the assessment and rating of ataxia and compared them with those of SCA6 patients. The age at onset was much higher in 16q-ADCA patients (60.1 +/- 9.8 years, n = 66) than in SCA6 patients (41.1 +/- 8.7 years, n = 35). Clinical features of 16q-ADCA were basically consistent with pure cerebellar ataxia, as well as in SCA6, but gaze-evoked nystagmus was observed less frequently in 16q-ADCA patients than in SCA6 patients. When compared at almost the same disease duration after onset, the severity of cerebellar ataxia was a little higher, and the progression rate seemed more rapid in 16q-ADCA patients than in SCA6 patients, but the differences were not significant.

Current and Promising Therapies in Autosomal Recessive Ataxias.

BACKGROUND & OBJECTIVE: 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. CONCLUSION: 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.

A diagnostic decision tree for adult cerebellar ataxia based on pontine magnetic resonance imaging.

Cerebellar ataxias (CAs) are heterogeneous conditions often require differential diagnosis. This study aimed to establish a diagnostic decision tree for differentiating CAs based on pontine MRI findings. Two-hundred and two consecutive ataxia patients were clinically classified into 4 groups: (1) spinocerebellar ataxia (SCA) with brainstem involvement (SCA-BSI), (2) Pure cerebellar SCA, (3) cerebellar dominant multiple system atrophy (MSA-c), and (4) Other CA. Signal intensity in pons was graded into 3 types: hot cross bun sign (HCBS), pontine midline linear T2-hyperintensity (PMH), or normal. The distance ratio of pontine base to tegmentum, named "BT-ratio", was measured. The presence of HCBS indicated either MSA-c with a specificity of 97.7%, or SCA2. When PMH was observed, a BT-ratio above 3.54 strongly indicated SCA-BSI, namely Machado-Joseph disease, SCA1, or dentatorubral-pallidoluysian atrophy, whereas a BT-ratio below 3.54 indicated MSA-c or SCA2. When the signal intensity was normal, a BT-ratio above 3.52 indicated SCA-BSI, whereas a BT-ratio below 3.52 suggested Pure cerebellar SCA or Other CA with pure cerebellar type. The decision tree was confirmed useful in a different 30 CA patients. We propose that differential diagnosis of CAs can be supported by combining pontine MRI signal intensity changes and BT-ratio.

Altered soleus responses to magnetic stimulation in pure cerebellar ataxia.

OBJECTIVE: Transcranial magnetic stimulation (TMS) over the leg motor area elicits a soleus primary response (SPR) and a soleus late response (SLR). We evaluated the influence of the cerebellofugal pathway on the SPR and SLR in patients with 'pure' cerebellar ataxia. METHODS: SPRs and SLRs were recorded from 11 healthy subjects and 9 patients with 'pure' cerebellar cortical degeneration; 5 with spinocerebellar ataxia type 6 (SCA6), and 4 with late cortical cerebellar ataxia (LCCA). In addition, three patients with localized cerebellar lesions were tested. RESULTS: The SPR latency was significantly longer in patients than in controls, but primary responses in the tibialis anterior muscle were normal. The frequency of abnormal SLR was 38.9% in the supine position and 83.3% in the standing position. Two out of three patients with localized cerebellar lesions also showed abnormal SLR. CONCLUSIONS: Altered SPRs in patients may result from a dysfunction of the primary motor cortex caused by crossed cerebello-cerebral diaschisis. In addition, our results suggest that 'pure' cerebellar degeneration involves the mechanism responsible for evoking SLR which is related to the control of posture. SIGNIFICANCE: SLR can be a useful neurophysiological parameter for evaluating cerebellofugal function.

[Autosomal recessive cerebellar ataxias with oculomotor apraxia]. / Les ataxies cérébelleuses autosomiques récessives avec apraxie oculomotrice.

INTRODUCTION: Autosomal recessive cerebellar ataxias (ARCA) comprise a phenotypically and genetically heterogeneous group of diseases. Recently, a subgroup of ARCA associated with oculomotor apraxia has been delineated. STATE OF THE ART: The ataxias with oculomotor apraxia (AOA) include four distinct genetic entities at least: ataxia-telangiectasia, ataxia telangiectasia-like disorder, ataxia with oculomotor apraxia type 1 (AOA1) and type 2 (AOA2). The responsible genes, ATM, MRE11, APTX and SETX respectively, are implicated in DNA-break repair mechanisms. CONCLUSION: We describe the phenotypic and genetic characteristics of these ataxias, based on a review of the literature and a personal study of AOA1 and AOA2 patients.

[Non-progressive congenital ataxias]. / Ataxias congénitas no progresivas.

INTRODUCTION: Non-progressive congenital ataxias (NPCA) constitute a heterogeneous group of processes linked to diverse aetiological factors that can be either environmentally or genetically determined. The signs of cerebellar compromise, which are preceded by unspecific signs such as early hypotonia, difficulty in sucking or chewing or retarded motor acquisition, become apparent with development or may remain absent when the disorder is very severe. DEVELOPMENT: NPCA can be accompanied by a number of pathologies and their diagnosis can be made easier by the concurrence of symptoms or signs of extra-cerebellar involvement, such as dysmorphic features or abnormalities affecting the skin, heart, bones, blood, eyes or other areas of the central or peripheral nervous system. Neuroimaging usually reveals vermian hypoplasia and/or hypoplasia of the cerebellar hemispheres, but can be normal in certain situations. The article includes a review of the NPCA following the classification proposed by Steinlin in 1998. CONCLUSIONS: The difficulties inherent in diagnosing these processes makes it necessary to deploy a wide range of complementary examinations, especially metabolic tests, before a generic diagnosis of NPCA can be established. Although the progress made in molecular genetics has made it possible to categorise NPCA better, both their causation and their hereditary or sporadic nature remain unknown in about 50% of cases.

[Autosomal recessive cerebellar ataxias. Their classification, genetic features and pathophysiology]. / Ataxias cerebelosas autosómicas recesivas. Clasificación, aspectos genéticos y fisiopatología.

INTRODUCTION AND DEVELOPMENT: Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs. They use to have early onset before the age of 20. Based on pathogenic mechanisms five main types may be distinguished: congenital (developmental disorder), mitochondrial ataxias, ataxias associated with metabolic disorders, ataxias with a DNA repair defect, and degenerative ataxia with unknown pathogenesis. The most frequent in Caucasian population are Friedreich ataxia and ataxia-telangiectasia. Other forms are much less common, and include abetaliproteinemia, ataxia with vitamin E deficiency (AVED), ataxia with oculomotor apraxia types 1 (AOA1) and 2 (AOA2), early onset cerebellar ataxia with retained reflexes, Charlevoix-Saguenay spastic ataxia, and Joubert syndrome. The prevalence of ARCA has been estimated to 7 in 100,000 inhabitants. These diseases are due to mutations in specific genes, some of which and its encoded proteins have been identified, such as FRDA (frataxin) in Friedreich ataxia, APTX (aprataxin) in AOA1, alphaTTP (alpha-tocopherol transfer protein) in AVED, and STX (senataxin) in AOA2. Due to autosomal recessive inheritance, previous familial history of affected individuals unlikely. CONCLUSIONS: Most of these cerebellar ataxias have no specific treatment with exception of the ataxia associated with deficiency coenzyme Q10 and abetalipoproteinemia. Clinical diagnosis must be confirmed by ancillary tests such as neuroimaging (magnetic resonance, scanning), electrophysiological examination, and mutation analysis when the causative gene has been identified. Correct clinical and genetic diagnosis is important for appropriate prognosis and genetic counseling and, in some instances, pharmacological treatment.

The inherited episodic ataxias: how well do we understand the disease mechanisms?

The past few years have seen the elucidation of several neurological diseases caused by inherited mutations of ion channels. In contrast to many other types of genetic disorders, the "channelopathies" can be studied with high precision by applying electrophysiological methods. This review evaluates the success of this approach in explaining the mechanisms of two forms of episodic ataxia that are known to be caused by mutations of ion channels: episodic ataxia type 1 (EA1, caused by K+ channel mutations) and episodic ataxia type 2 (EA2, caused by Ca2+ channel mutations). Although both of these disorders are rare, they raise many important questions about the roles of identified channels in brain function. Indeed, a resolution of the mechanisms by which both diseases occur will represent a major milestone in understanding diseases of the CNS, in addition to opening the way to novel possible treatments.