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Objective: This study aims to evaluate our experience in the diagnosis of hereditary ataxias (HAs), to analyze data from a real-world scenario. Study design: This is a retrospective, cross-sectional, descriptive study conducted at a single Italian adult neurogenetic outpatient clinic, in 147 patients affected by ataxia with a suspicion of hereditary forms, recruited from November 1999 to February 2024. A stepwise approach for molecular diagnostics was applied: targeted gene panel (TP) next-generation sequencing (NGS) and/or clinical exome sequencing (CES) were performed in the case of inconclusive first-line genetic testing, such as short tandem repeat expansions (TREs) testing for most common spinocerebellar ataxias (SCA1-3, 6–8,12,17, DRPLA), other forms [Fragile X-associated tremor/ataxia syndrome (FXTAS), Friedreich ataxia (FRDA) and mitochondrial DNA-related ataxia, RFC1-related ataxia/CANVAS] or inconclusive phenotype-guided specific single gene sequencing. Result: A definitive diagnosis was reached in 36.7% of the cases. TREs testing was diagnostic in 30.4% of patients. The three most common TREs ataxias were FRDA (36.1%), SCA2 (27.8%), and RFC1-related ataxia/CANVAS (11.1%). In five patients, the molecular diagnosis was achieved by single gene sequencing and causative mutations were identified in POLG (2), SACS (1), DARS2 (1), MT-ATP6 (1). Of 94 patients with a suspicion of HAs of indeterminate genetic origin, 68 underwent new molecular evaluation using the NGS approach. In 28 of these cases, CES was performed after the TP sequencing resulted negative. In 13 patients, the diagnosis was achieved by NGS approach. In 7 of these 13 patients, the diagnosis was made by CES. Genes mutations identified as causative of HAs were found in SPG7 (4), SACS (1), CACNA1A (1), CACNA1G (1), EEF2 (1), PRKCG (1), KCNC3 (1), ADCK3 (1), SYNE1 (1), ITPR1 (1). A positive family history of ataxia and early onset of symptoms were associated with a higher likelihood of obtaining a definite diagnosis. Conclusion: The molecular diagnosis of HAs remains a significant challenge for neurologists. Our data indicate that, in most cases, a diagnosis of HA can be established through first line genetic testing, particularly TREs testing. However, for patients with a clinical diagnosis of HA who do not achieve a molecular diagnosis through initial genetic tests, the use of NGS proves to be a valuable tool, providing a definitive diagnosis in approximately 20% of cases. Therefore, when feasible in clinical practice, integrating NGS testing, especially exome sequencing, into the diagnostic decision-making process for unsolved cases is crucial. [ABSTRACT FROM AUTHOR]

The last decade has witnessed major breakthroughs in identifying novel genetic causes of hereditary ataxias, deepening our understanding of disease mechanisms, and developing therapies for these debilitating disorders. This article reviews the currently approved and most promising candidate pharmacotherapies in relation to the known disease mechanisms of the most prevalent autosomal recessive ataxias. Omaveloxolone is an Nrf2 activator that increases antioxidant defense and was recently approved for treatment of Friedreich ataxia. Its therapeutic effect is modest, and further research is needed to find synergistic treatments that would halt or reverse disease progression. Promising approaches include upregulation of frataxin expression by epigenetic mechanisms, direct protein replacement, and gene replacement therapy. For ataxia-telangiectasia, promising approaches include splice-switching antisense oligonucleotides and small molecules targeting oxidative stress, inflammation, and mitochondrial function. Rare recessive ataxias for which disease-modifying therapies exist are also reviewed, emphasizing recently approved therapies. Evidence supporting the use of riluzole and acetyl-leucine in recessive ataxias is discussed. Advances in genetic therapies for other neurogenetic conditions have paved the way to implement feasible approaches with potential dramatic benefits. Particularly, as we develop effective treatments for these conditions, we may need to combine therapies, consider newborn testing for pre-symptomatic treatment, and optimize non-pharmacological approaches. [ABSTRACT FROM AUTHOR]

Background: Spinocerebellar ataxia 17 (SCA17) is a rare autosomal dominant form of inherited ataxia, caused by heterozygous trinucleotide repeat expansions encoding glutamine in the TATA box-binding protein (TBP) gene. Case description: We describe the clinical history, neuropsychological, and neuroimaging findings of a 42-year-old patient who presented for medical attention showing prevalent behavioral and cognitive problems along with progressively worsening gait disturbances. The patient's family history indicated the presence of SCA17 in the maternal lineage. Genetic analysis confirmed a heterozygous 52-CAG pathological expansion repeat in TBP (normal interval, 25–40 CAG. Brain 18-fluorodeoxyglucose positron emission tomography (FDG-PET) showed bilateral hypometabolism in the sensorimotor cortex, with a slight predominance on the right, as well as in the striatal nuclei and thalamic hypermetabolism, a finding similar to what is observed in Huntington's disease. The patient also underwent neuropsychological evaluation, which revealed mild cognitive impairment and difficulties in social interaction and understanding other's emotions (Faux Pas Test and Reading the Mind in the Eyes Test). Conclusion: Our report emphasizes the importance of considering SCA17 as a possible diagnosis in patients with a prevalent progressive cognitive and behavioral disorders, even with a pattern of FDG-PET hypometabolism not primarily indicative of this disease. [ABSTRACT FROM AUTHOR]

Background: Core stability exercises (CSE) have been shown to be effective in improving trunk function in several neurological diseases, but the evidence is scarce on Hereditary Ataxias (HA). Objective: To evaluate the effectiveness of a 5‐week home‐based CSE program in terms of ataxia severity, trunk function, balance confidence, gait speed, lower limb motor function, quality of life, health status and falls rate in HA individuals at short‐ and long‐term. Methods: This is an assessor‐blind randomized controlled clinical trial parallel group 1:1. The individuals were divided in experimental group (EG) performed standard care in addition to CSE, and control group (CG) performed standard care alone. The CSE home‐program was conducted 1‐h/day, 5‐day/week for 5‐week. The assessment was performed at baseline, endpoint (5‐week), and follow‐up (10‐week). The primary outcomes were ataxia severity assessed by the Scale for the Assessment and Rating of Ataxia and trunk function assessed by Spanish‐version of Trunk Impairment Scale 2.0. The secondary outcomes were balance confidence assessed by Activities‐specific Balance Confidence (ABC), gait speed by 4‐meter walk test (4‐MWT), the lower limb motor function by 30‐s sit‐to‐stand, quality of life by EuroQol 5‐dimension 5‐level (EQ‐5D‐5L), health‐status by EQ‐5D and falls rate. Results: Twenty‐three HA individuals were recruited (51.8 ± 11.10 years). Statistically significant group‐time interaction was shown in ABC (F:5.539; P = 0.007), EQ‐5D‐5L Total (F:4.836; P = 0.013), EQ 5D (F:7.207; P = 0.006). Conclusions: No statistical differences between groups for ataxia severity and trunk function were observed. However, were differences for balance confidence, gait speed, quality of life, and falls rate in HA individuals. [ABSTRACT FROM AUTHOR]

Sleep disturbances are common in various neurological pathologies, including amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), hereditary ataxias, Huntington's disease (HD), progressive supranuclear palsy (PSP), and dementia with Lewy bodies (DLB). This article reviews the prevalence and characteristics of sleep disorders in these conditions, highlighting their impact on patients' quality of life and disease progression. Sleep-related breathing disorders, insomnia, restless legs syndrome (RLS), periodic limb movement syndrome (PLMS), and rapid eye movement sleep behavior disorder (RBD) are among the common sleep disturbances reported. Both pharmacological and non-pharmacological interventions play crucial roles in managing sleep disturbances and enhancing overall patient care. [ABSTRACT FROM AUTHOR]

Background: Verbal fluency tests (VFTs) are widely used to assess cognitive-linguistic performance in neurological diseases. However, the influence of dysarthria on performance in tests requiring oral responses is unclear in ataxia and Parkinson's disease. Objectives: To determine the impact of dysarthria on VFT performance and evaluate the validity and reliability of alternative methods for analyzing VFT data. Method: Trained raters evaluated dysarthria using VFT recordings in people with ataxia (N = 61) or Parkinson's disease (PD; N = 69). Total Correct Items scores and qualitative parameters (intrusions, ambiguous verbalizations, perseverations, and interjections) were compared across semantic, phonemic, and alternating fluency tasks. Disease severity was considered as a covariate in the regression model. Results: VFT dysarthria ratings correlated with the benchmark (ground truth) dysarthria scores derived from a monologue. Ambiguous responses resulting from unclear speech impeded the rater's ability to determine if a response was correct. Regression analysis indicated that more severe dysarthria ratings predicted diminished scores in all three tasks (semantic fluency, phonemic fluency and alternating fluency) in the ataxia group. The contribution of disease severity to semantic, phonemic and alternating fluency was reduced substantially in the ataxia group after accounting for dysarthria severity in the model in both groups. Conclusions: Dysarthria severity can be estimated based on speech samples derived from VFT. Dysarthria can lead to lower total correct items and is associated with more ambiguous verbalizations in VFT. Dysarthria severity should be considered when interpreting VFT performance in common movement disorders. [ABSTRACT FROM AUTHOR]

Objective: To determine the effectiveness of transcranial magnetic stimulation in improving cerebellar ataxia. Data sources: PubMed, EMBASE, the Cochrane Library, Springer, Science Direct, the China National Knowledge Infrastructure (CNKI) and the China Science and Technology Journal Database (VIP) were searched until 2022. Review methods: Trials with transcranial magnetic stimulation on the effects on cerebellar ataxia were included, and the effect size was evaluated using the standardized mean difference (SMD) or mean difference (MD) and a 95% confidence interval (CI). Results: Eight studies comprising 272 participants, published between 2014 and 2022, were included. The results revealed that the effect of TMS on patients with cerebellar ataxia as assessed by the International Cooperative Ataxia Rating Scale (ICRAS), the Scale for the Assessment and Rating of Ataxia (SARA), the Berg Balance Scale (BBS), and the Timed Up and Go (TUG) test was statistically significant (P < 0.01) with low heterogeneity among the studies (I2 = 4, 27, 0, and 0% respectively). Conclusion: The effects of transcranial magnetic stimulation in improving cerebellar ataxia in the affected patients are significant. TMS targeting the cerebellar structures can induce changes in the excitability of the cerebellar-thalamus-cortical pathways; thus, it is necessary to carry out large-scale research with good design and high quality in the future. [ABSTRACT FROM AUTHOR]

Hereditary ataxias (HA) are a rare group of heterogeneous disorders. Here, we present the results of molecular testing of a group of ataxia patients using a custom-designed next-generation sequencing (NGS) panel. Due to the genetic and clinical overlapping of hereditary ataxias and spastic paraplegias (HSP), the panel encompasses together HA and HSP genes. The NGS libraries, comprising coding sequences for 152 genes, were performed using KAPA HyperPlus and HyperCap Target Enrichment Kit, sequenced on the MiSeq instrument. The results were analyzed using the BaseSpace Variant Interpreter and Integrative Genomics Viewer. All pathogenic and likely pathogenic variants were confirmed using Sanger sequencing. A total of 29 patients with hereditary ataxias were enrolled in the NGS testing, and 16 patients had a confirmed molecular diagnosis with diagnostic accuracy rate of 55.2%. Pathogenic or likely pathogenic mutations were identified in 10 different genes: POLG (PEOA1, n = 3; SCAE, n = 2), CACNA1A (EA2, n = 2), SACS (ARSACS, n = 2), SLC33A1 (SPG42, n = 2), STUB1 (SCA48, n = 1), SPTBN2 (SCA5, n = 1), TGM6 (SCA35, n = 1), SETX (AOA2, n = 1), ANO10 (SCAR10, n = 1), and SPAST (SPG4, n = 1). We demonstrated that an approach based on the targeted use of the NGS panel can be highly effective and a useful tool in the molecular diagnosis of ataxia patients. Furthermore, we highlight the fact that a sequencing panel targeting both ataxias and HSP genes increases the diagnostic success level. [ABSTRACT FROM AUTHOR]

Objective. This study aimed to identify functional outcomes related to independence in walking among people affected by hereditary ataxias. Methods. Sixty participants were selected by convenience in a list provided by an organization of people with ataxia. Sociodemographic and clinical data were collected using a semistructured questionnaire. The Assessment and Rating of Ataxia was used to assess and rate cerebellar ataxia. Changes in body structure and function, limitation in activities, and restriction in participation were evaluated with specific outcome measures. Participants were classified as independent in walking if they were able to walk without walking aids or human assistance and as dependent in walking if they have been using walking aids (sticks, crutches, or walkers) for more than 6 months, using a wheelchair for locomotion most of the day, or both. Multivariate logistic regression analyses were conducted hierarchically and in blocks considering upper limbs function, balance systems, sensory functions, postural control, walking, independence, cognition, and perception as independent variables. The prevalence ratio for walking independence was determined. Results. The final regression model pointed out that gait capacity assessed by the 6-Minute Walk Test and dexterity assessed by the Box and Blocks test were the main markers related to walking independence in individuals with hereditary ataxias. Conclusion. The distance covered in 6 minutes of walking (walking endurance) and upper extremity dexterity can be used to better assess the progression of cerebellar disease related to walking independence in individuals with hereditary ataxias. Impact. This study supports early detection of individuals who are at risk of loss of walking independence and an optimized rehabilitation plan. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxias type 1 (SCA1) is an autosomal dominant disease usually manifesting in adulthood. We performed a prospective 1-year longitudinal study in 14 presymptomatic mutation carriers (preSCA1), 11 ataxic patients, and 21 healthy controls. SCA1 patients had a median disease duration of 6 years (range 2–16) and SARA score of 7 points (range 3.5–20). PreSCA1 had an estimated time before disease onset of 9.7 years (range 4–30), and no signs of ataxia. At baseline, SCA1 patients significantly differed from controls in SARA score (Scale for Assessment and Rating of Ataxia), cognitive tests, and structural MRI measures. Significant volume loss was found in cerebellum, brainstem, basal ganglia, and cortical thinning in frontal, temporal, and occipital regions. PreSCA1 did not differ from controls. At 1-year follow-up, SCA1 patients showed significant increase in SARA score, and decreased volume of cerebellum (− 0.6%), pons (− 5.5%), superior cerebellar peduncles (− 10.7%), and midbrain (− 3.0%). Signs of disease progression were also observed in preSCA1 subjects, with increased SARA score and reduced total cerebellar volume. Our exploratory study suggests that clinical scores and MRI measures provide valuable data to monitor and quantify the earliest changes associated with the preclinical and the symptomatic phases of SCA1 disease. [ABSTRACT FROM AUTHOR]

This paper reviews and summarizes three main aspects of spinocerebellar ataxias (SCA) in the Asian population. First, epidemiological studies were comprehensively reviewed. Overall, the most common subtypes include SCA1, SCA2, SCA3, and SCA6, but there are large differences in the relative prevalence of these and other SCA subtypes between Asian countries. Some subtypes such as SCA12 and SCA31 are rather specific to certain Asian populations. Second, we summarized distinctive phenotypic manifestations of SCA patients of Asian origin, for example a frequent co-occurrence of parkinsonism in some SCA subtypes. Lastly, we have conducted an exploratory survey study to map SCA-specific expertise, resources, and management in various Asian countries. This showed large differences in accessibility, genetic testing facilities, and treatment options between lower and higher income Asian countries. Currently, many Asian SCA patients remain without a final genetic diagnosis. Lack of prevalence data on SCA, lack of patient registries, and insufficient access to genetic testing facilities hamper a wider understanding of these diseases in several (particularly lower income) Asian countries. [ABSTRACT FROM AUTHOR]

Many neurodegenerative diseases are defi ned by the aggregation and accumulation of the specifi c pathological protein in the CNS, leading to irreversible and fatal changes of the tissues. However, due to high clinical and epidemiological heterogeneity, a defi nitive ante-mortem dia gnosis is very difficult to perform. The definitive diagnosis is confirmed by neuropathological evaluation made only at autopsy. Hope for early and accurate laboratory diagnostics of these diseases within a patient’s life represents methods based on the detection of seeding activity of pathological proteins. An example is a highly specific and ultrasensitive new method called Real-Time Quaking- Induced Conversion (RT-QuIC) assay. Originally, RT-QuIC was developed for the diagnosis of prions showing 92–97% sensitivity and 100% specificity. In our laboratory, we were able to detect prions in 39 brain samples, corresponding 24 cerebrospinal fluid samples, and in 38 skin samples of patients with Creutzfeldt-Jakob disease using RT-QuIC. Lately, the use of the RT-QuIC method for detection of pathological protein α-synuclein, which accumulates during Parkinson’s disease or dementia with Lewy bodies, and tau protein which is characteristic for Alzheimer’s disease or corticobasal degeneration, was described. This review aims to elucidate the dia gnosis of neurodegenerative diseases and its recent approaches using RT-QuIC. [ABSTRACT FROM AUTHOR]

Background: Genetic pediatric ataxias are heterogeneous rare disorders, mainly inherited as autosomal‐recessive traits. Most forms are progressive and lack effective treatment, with relevant socioeconomical impact. Albeit ataxia represents the main clinical feature, the phenotype can be more complex, with additional neurological and nonneurological signs being described in several forms. Methods and Results: In this review, we provide an overview of the occurrence and spectrum of movement disorders in the most relevant forms of childhood‐onset genetic ataxias. All types of hypokinetic and hyperkinetic movement disorders of variable severity have been reported. Movement disorders occasionally represent the symptom of onset, predating ataxia even of a few years and therefore challenging an early diagnosis. Their pathogenesis still remains poorly defined, as it is not yet clear whether movement disorders may directly relate to the cerebellar pathology or result from an extracerebellar dysfunction, including the basal ganglia. Conclusion: Recognition of the complete movement disorder phenotype in genetic pediatric ataxias has important implications for diagnosis, management, and genetic counseling. [ABSTRACT FROM AUTHOR]

The prevalence estimations of hereditary ataxias are biased since most epidemiological studies are confined to isolated geographical regions and few nationwide studies are available. The study aims to assess the prevalence, distribution, and neurological features of the Cuban population with hereditary ataxias. A nationwide epidemiological study of hereditary ataxias was conducted in Cuba between March 2017 and June 2018. Patients were scheduled at the Cuban ataxia research center, various hospitals, or at their homes. Demographic and clinical variables were obtained through standardized questionnaires and validated clinical tools. Overall, 1001 patients were diagnosed with hereditary ataxias for a nationwide prevalence of 8.91 cases/100.000 inhabitants. Spinocerebellar ataxia type 2 (SCA2) was the commonest subtype, with highest prevalences at Holguín province (47.86/100.000), and a broad dissemination in the whole country. Most of neurological features were common between all SCA cohorts, but the frequencies of some of them varied between distinct subtypes. Within the SCA2 cohort, significant influences of long mutation size and higher disease duration over the muscle atrophy and oculomotor disorders were observed. Besides, higher disease durations were associated with resting tremor and dysphagia, whereas shorter disease durations were associated with hyperreflexia. The spreading of SCA2 to whole country and the documented raising of its prevalence set the rationales for higher-scope medical care and research strategies, supported in collaborative research networks. The wide epidemiological, clinical, and genetic characterization of this founder SCA2 population identifies this homogeneous cohort as an attractive source for the development of future clinical-genetic and therapeutic researches. [ABSTRACT FROM AUTHOR]

Background: The frequency and presentation of each of the most common forms of spinocerebellar ataxias (SCAs) varies widely. In the case of the Americas, this diversity is particularly dynamic given additional social, demographic, and cultural characteristics. Objective: To describe the regional prevalence and clinical phenotypes of SCAs throughout the continent. Methods: A literature search was performed in both MEDLINE and LILACS databases. The research was broadened to include the screening of reference lists of systematic review articles for additional studies. Investigations dating from the earliest available through 2019. Only studies in English, Portuguese, and Spanish were included. We analyzed publications with genetically confirmed cases only, ranging from robust samples with epidemiological data to case reports and case series from each country or regions. Results: Overall, SCA3 is the most common form in the continent. Region‐specific prevalence and ranking of the common forms vary. On the other hand, region‐specific phenotypic variations were not consistently found based on the available literature analyzed, with the exception of the absence of epilepsy in SCA10 consistently described in a particular cluster of cases in South Brazil. Conclusion: Systematic, multinational studies analyzing in detail the true frequencies of SCAs across the Americas as well as distinct clinical signs and clues of each form would be ideal to look for these potential variations. [ABSTRACT FROM AUTHOR]

SYNE1 gene mutations were identified as a cause of late-onset pure cerebellar syndrome. Non-cerebellar symptoms, including cognitive impairment, were already described in this condition. The aim of this study was to perform a detailed cognitive and psychiatric description of patients with SYNE1 gene mutations. We performed neuropsychological and psychiatric evaluations of six patients with SYNE1 ataxia and compared their performance with 18 normal controls paired for age and education level. SYNE1 ataxia patients present cognitive dysfunction, characterized by impairment in attention and processing speed domains. Otherwise, the psychiatric assessment reported low levels of overall behavioral symptoms with only some minor anxiety-related complaints. Although this is a small sample of patients, these results suggest that SYNE1 ataxia patients may represent a model to investigate effects of cerebellar degeneration in higher hierarchical cognitive functions. For further studies, abstract thinking impairment in schizophrenia may be related to dysfunction in cerebellum pathways. [ABSTRACT FROM AUTHOR]

Transcranial magnetic stimulation (TMS) is a valuable technique to assess and modulate human brain function in normal and pathological conditions. This critical review surveys the contributions of TMS to the diagnosis, insight into pathophysiology and treatment of genetically confirmed hereditary ataxias, a heterogeneous group of neurodegenerative disorders that can affect motor cortex and the corticospinal tract. Most studies were conducted on small sample sizes and focused on diagnostic approaches. The available data demonstrate early involvement of the corticospinal tract and motor cortex circuitry, and support the possible efficacy of cerebellar repetitive TMS (rTMS) as therapeutic approach. Further TMS-based studies are warranted, to establish biomarkers for early diagnosis and disease monitoring, explore the involvement of the cerebello-dentato-thalamo-cortical projection, study the effects of rTMS-induced plasticity, and utilize rTMS for treatment. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia that occurs as a consequence of abnormal CAG expansions in the ATXN2 gene. Progressive clinical features result from the neurodegeneration of cerebellum and extra-cerebellar structures including the pons, the basal ganglia, and the cerebral cortex. Clinical, electrophysiological, and imaging approaches have been used to characterize the natural history of the disease, allowing its classification into four distinct stages, with special emphasis on the prodromal stage, which is characterized by a plethora of motor and non-motor features. Neuropathological investigations of brain tissue from SCA2 patients reveal a widespread involvement of multiple brain systems, mainly cerebellar and brainstem systems. Recent findings linking ataxin-2 intermediate expansions to other neurodegenerative diseases such as amyotrophic lateral sclerosis have provided insights into the ataxin-2-related toxicity mechanism in neurodegenerative diseases and have raised new ethical challenges to molecular predictive diagnosis of SCA2. No effective neuroprotective therapies are currently available for SCA2 patients, but some therapeutic options such as neurorehabilitation and some emerging neuroprotective drugs have shown palliative benefits.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia that occurs as a consequence of abnormal CAG expansions in the ATXN2 gene. Progressive clinical features result from the neurodegeneration of cerebellum and extra-cerebellar structures including the pons, the basal ganglia, and the cerebral cortex. Clinical, electrophysiological, and imaging approaches have been used to characterize the natural history of the disease, allowing its classification into four distinct stages, with special emphasis on the prodromal stage, which is characterized by a plethora of motor and non-motor features. Neuropathological investigations of brain tissue from SCA2 patients reveal a widespread involvement of multiple brain systems, mainly cerebellar and brainstem systems. Recent findings linking ataxin-2 intermediate expansions to other neurodegenerative diseases such as amyotrophic lateral sclerosis have provided insights into the ataxin-2-related toxicity mechanism in neurodegenerative diseases and have raised new ethical challenges to molecular predictive diagnosis of SCA2. No effective neuroprotective therapies are currently available for SCA2 patients, but some therapeutic options such as neurorehabilitation and some emerging neuroprotective drugs have shown palliative benefits. [ABSTRACT FROM AUTHOR]

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Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease caused by a CAG repeat expansion in the ATXN2 gene. Cuba has the highest prevalence (6.57 cases/10 inhabitants) of SCA2 in the world. The existence of 753 affected individuals and 7173 relatives at risk prompted the development in 2001 of the first predictive testing program in the country. The medical records of over 1193 individuals, who requested the test within a 13-year period, were analyzed retrospectively. The presymptomatic and the prenatal tests had uptake rates of 43.4 and 23.9 %, respectively. Several ethical challenges resulted from this program. These include the following: (1) withdrawal due to the initial protocol's length; (2) the request to participate by 16 at-risk adolescents; (3) the decision made by ten out of 33 couples with a test-positive fetus to carry the pregnancy to term, leading to de facto predictive testing of minors; (4) the elevated frequency of the ATXN2 gene large normal alleles (≥23 to 31 repeats) in the reference population. These issues have led to major changes in the guidelines of the predictive testing protocol: (1) the protocol length was shortened; (2) the inclusion criteria were expanded to reach at-risk adolescents with an interest in prenatal diagnosis; (3) interdisciplinary follow-up was offered to families in which test-positive fetuses were not aborted; (4) prenatal testing was made available to carriers of large normal alleles with ≥27 CAG repeats. The profiles of the participants were similar to those reported for other predictive testing programs for conditions like Huntington disease and familial adenomatous polyposis. The genetic counseling practices at the community level, the ample health education provided to the at-risk population, together with multidisciplinary and specialized attention to the affected families, are lessons from the Cuban experience that can be relevant for other international teams conducting predictive testing for other late-onset neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Our objective was to determine whether substantia nigra (SN) hyperechogenicity is greater in spinocerebellar ataxias (SCA) with nigrostriatal affectation than in ataxias without it. A cross-sectional case-control study analyzing four groups of patients was conducted: 1) nigrostriatal ataxias (SCA3 and SCA6), 2) nigrostriatal healthy controls matched by age and sex, 3) non-nigrostriatal ataxias (FRDA and SCA7), and 4) non-nigrostriatal healthy controls matched by age and sex. All the patients underwent a transcranial ultrasound performed by an experienced sonographer blinded to the clinical, genetic, and neuroimaging data. The SN area was measured and compared in the four groups. The SN area was also correlated with clinical features and genetic data in the two ataxia groups. We examined 12 patients with nigrostriatal ataxia (11 SCA3 and 1 SCA6), 12 nigrostriatal healthy control patients, 7 patients with non-nigrostriatal ataxia (5 FRDA and 2 SCA7), and 7 non-nigrostriatal healthy control patients. The median (IQR) SN area (cm) was greater in the nigrostriatal ataxias compared with the controls (right SN, 0.43 [0.44] vs. 0.11 [0.25]; P = 0.001; left SN, 0.32 [0.25] vs. 0.11 [0.16]; P = 0.001), but was similar among the non-nigrostriatal ataxias and controls. There were no statistically significant differences in the SN area between the nigrostriatal and non-nigrostriatal ataxias, although there was a tendency for a greater left SN area in the nigrostriatal compared with the non-nigrostriatal ataxias (0.32 [0.25] vs. 0.16 [0.24], P = 0.083). SN echogenicity is markedly greater in ataxias with nigrostriatal pathology than in controls. The role of SN hyperechogenicity in differentiating ataxias with and without nigrostriatal pathology should be elucidated in future studies. [ABSTRACT FROM AUTHOR]

Herein, we report a patient that presented with late-onset progressive steppage gait, neuropathy and pes cavus, suggesting Charcot-Marie-Tooth (CMT) disease. Subsequent genetic investigation confirmed Friedreich's ataxia (FRDA). We demonstrate that late-onset Friedreich's ataxia (LOFA) may be a CMT mimicker. This case reinforces that other genetic conditions may clinically resemble CMT. The clinical similarities between CMT and FRDA include a symmetrical neuropathy (axonal in FRDA), steppage gait, and eventually scoliosis. We suggest that late-onset forms of hereditary neuropathies should be carefully evaluated, since LOFA may be a CMT mimicker. [ABSTRACT FROM AUTHOR]

Autosomal recessive inherited ataxias are a growing group of genetic disorders. We report two Italian siblings presenting in their mid-50s with difficulty in walking, dysarthria and progressive cognitive decline. Visual loss, ascribed to glaucoma, manifested a few years before the other symptoms. Brain MRI showed severe cerebellar atrophy, prevalent in the vermis, with marked cortical atrophy of both hemispheres. Exome sequencing identified a novel homozygous mutation (c.935G > A;p.Ser312Asn) in the ceroid neuronal lipofuscinosis type 5 gene ( CLN5). Bioinformatics predictions and in vitro studies showed that the mutation was deleterious and likely affects ER-lysosome protein trafficking. Our findings support CLN5 hypomorphic mutations cause autosomal recessive cerebellar ataxia, confirming other reports showing CLN mutations are associated with adult-onset neurodegenerative disorders. We suggest CLN genes should be considered in the molecular analyses of patients presenting with adult-onset autosomal recessive cerebellar ataxia. [ABSTRACT FROM AUTHOR]

OBJECTIVE To study hereditary ataxias in the Greek population, focusing on the prevalence, geographical distribution and phenotypic and genotypic spectrum of Friedreich's ataxia and dominant ataxias, also known as spinocerebellar ataxias (SCA). METHOD The study included 192 consecutive index patients with suspected hereditary ataxia referred to the Neurogenetics Unit of the Eginition Hospital, Athens over a period of 19 years. For prevalence estimates all non-index patients still alive from the Athens cohort were included, along with a small group of patients with ataxia referred to the Cyprus Institute of Neurology and Genetics for molecular diagnosis. RESULTS The minimum prevalence of Friedreich's ataxia was estimated at 0.9/100,000. A higher prevalence was noted in the Aegean islands, with clusters of very high prevalence in the islands of Ikaria and Melos. The minimum prevalence for SCA was 0.7/100,000. The genotypic and phenotypic spectrum of Friedreich's ataxia was not significantly different from that documented in other European populations; one patient was found to be a compound heterozygote for a known point mutation in FXN (Asn146Lys). Undiagnosed hereditary ataxias included a majority of Friedreich-like and spastic ataxias. Regarding the different SCA genetic subtypes, SCA1, SCA2, SCA6, SCA7 and SCA17 were identified, SCA1 and SCA7 being the most common dominant ataxias in this cohort, while no patient had SCA3, the most common SCA in many European populations. In total, a molecular diagnosis was reached in 30% of dominant ataxias. Undiagnosed SCA patients included a majority with type III dominant ataxias (pure ataxias). CONCLUSIONS Friedreich's ataxia is the commonest hereditary ataxia in the Greek population, with prevalence somewhat below the European average, and dominant SCAs are the second in frequency. Patients with SCA1, SCA2, SCA6, SCA7 and SCA17 comprise the spectrum of Greek patients with ataxia with a specific molecular diagnosis, but SCA3 (Machado-Joseph disease) appears to be very rare in the Greek population. Based on the above findings, a diagnostic algorithm is proposed for the molecular approach to hereditary ataxias in Greece. [ABSTRACT FROM AUTHOR]

In 2001 a program for predictive testing of Spinocerebellar Ataxia type 2 was developed in Cuba, based on the detection of an abnormal CAG trinucleotide repeat expansion in the ATXN2 gene. A descriptive study was designed to assess the implications of ATXN2 large normal and intermediate alleles in the context of the SCA2 Prenatal Diagnosis Program. Four clinical scenarios were selected based upon the behaviour of large normal and intermediate alleles when passing from one generation to the next, showing expansions, contractions, or stability in the CAG repeat size. In some populations, traditional Mendelian risk figures of 0 % or 50 % may not be applicable due to the high frequency of unstable large normal alleles. Couples with no family history of SCA2 may have a >0 % risk of having an affected offspring. Similarly, couples in which there is both an expanded and a large normal allele may have a recurrence risk >50 %. It is imperative that these issues be addressed with these couples during genetic counseling. These recurrence risks have to be carefully estimated in the presence of such alleles (particularly alleles ≥27 CAG repeats), carriers need to be aware of the potential risk for their descendants, and programs for prenatal diagnosis must be available for them. [ABSTRACT FROM AUTHOR]

Cuba reports the highest worldwide prevalence of spinocerebellar ataxia type 2 (SCA2) and the greatest number of descendants at risk. A protocol for genetic counseling, presymptomatic testing, and prenatal diagnosis of hereditary ataxias has been under development since 2001. Considering that the revision of the experience with prenatal diagnosis for SCA2 in Cuba would enable comparison of ours with international findings, we designed a descriptive study, based on the retrospective revision of the medical records belonging to the 58 couples that requested their inclusion in the program, during an 11-year period (2001-2011). Most of the participants in the prenatal diagnosis program were known presymptomatic carriers, diagnosed through the presymptomatic testing in the same period of study, for an uptake among them of 22.87 % (51 out of 223). In 28 cases, the fetuses were carriers, 20 of these couples (71.43 %) decided to terminate the pregnancy; the rest continued the pregnancy to term, this resulting in a predictive test for their unborn children. A predominance of females as the at-risk progenitor was observed. Except for a slightly lower average age, the results attained in the Cuban SCA2 prenatal diagnosis program resulted similar to the ones reported for Huntington disease in other countries. It is necessary to have easy access to the Cuban program through its expansion to other genetic centers along the island. Future research is needed to evaluate the long-term impact of both the predictive testing in unborn children and the selection of other reproductive options by the at-risk couples. [ABSTRACT FROM AUTHOR]

Having reported the world's highest prevalence of spinocerebellar ataxia type 2 ( SCA2), health professionals in Cuba developed a program for the predictive testing of this condition. Between February 2001 and December 2011, a total of 1050 individuals requested their inclusion in the presymptomatic testing (PST) program. Their medical records were retrospectively analyzed in the present descriptive study. A total of 768 participants completed the protocol, 204 withdrew and 78 were excluded. The PST uptake was 24.91%. Females predominated and 70.96% had negative test results. Their main motivations were risk assessment in their descendants, physical and psychological preparation to cope with the disease and planning for the future. The profile of Cuban participants in the predictive testing program is similar to the one reported for other programs all over the world, nevertheless the genetic counseling practice at the community level is a distinctive aspect, which is valuable in providing at-risk individuals with wide and proper knowledge before their testing inclusion request. The SCA2 predictive testing program has high uptake rates and is renowned in our population. Future research is needed to assess the long-term psychological impact in the participants, their partners and relatives. [ABSTRACT FROM AUTHOR]

Background: Hereditary ataxias (HA) comprise a group of genetically heterogeneous rare diseases. As important public health problems to be monitored, this study analyses the morbimortality of HA in Spain. Methods: Data were extracted from the national death index (1981-2008), using the International Classification of Diseases (ICD) 9th revision code 334 until 1998, and 10th revision code G11 from 1999 onwards. ICD-9 codes were then selected from the national discharge dataset (1998-2007). Age-adjusted morbidity and mortality rates were obtained by gender and 5-year period. Results: Of the 610 HA deaths from 1981 to 2008, 277 corresponded to Friedreich's ataxia (45.4%) and 333 (54.6%) to other and unspecified ataxias (non-Friedreich group). Both groups showed an increase in mortality trend, which was more pronounced in males from 1985-1989 to 1990-1994. Geographical distribution of mortality revealed higher risk for males, mainly in the north of Spain. A total of 5,341 HA hospitalisations were identified from 1998 to 2007. The average annual age-adjusted hospitalisation rate was 1.19 per 100,000 population, with a rising trend. Conclusion: This increase in morbidity and mortality, coupled with the slight interprovincial differences, indicate that more attention should be paid to these rare diseases by public authorities and society alike. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In this review, progress in clinical neurogenetics research published in the Journal of Neurology during the past year is summarized. [ABSTRACT FROM AUTHOR]

We aimed to perform a comprehensive systematic review of the existing ataxia scales. We described the disorders for which the instruments have been validated and used, the time spent in its application, its validated psychometric properties, and their use in studies of natural history and clinical trials. A search from 1997 onwards was performed in the MEDLINE, LILACS, and Cochrane databases. The web sites ClinicalTrials.gov and Orpha.net were also used to identify the endpoints used in ongoing randomized clinical trials. We identified and described the semiquantitative ataxia scales (ICARS, SARA, MICARS, BARS); semiquantitative ataxia and non-ataxia scales (UMSARS, FARS, NESSCA); a semiquantitative non-ataxia scale (INAS); quantitative ataxia scales (CATSYS 2000, AFCS, CCFS and CCFSw, and SCAFI); and the self-performed ataxia scale (FAIS). SARA and ICARS were the best studied and validated so far, and their reliability sustain their use. Ataxia and non-ataxia scores will probably provide a better view of the overall disability in long-term trials and studies of natural history. Up to now, no clear advantage has been disclosed for any of them; however, we recommend the use of specific measurements of gait since gait ataxia is the first significant manifestation in the majority of ataxia disorders and comment on the best scales to be used in specific ataxia forms. Quantitative ataxia scales will be needed to speed up evidence from phase II clinical trials, from trials focused on the early phase of diseases, and for secondary endpoints in phase III trials. Finally, it is worth remembering that estimation of the actual minimal clinically relevant difference is still lacking; this, together with changes in quality of life, will probably be the main endpoints to measure in future therapeutic studies. [ABSTRACT FROM AUTHOR]

Sleep disorders are common in neurodegenerative diseases such as Parkinson's disease (PD), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), hereditary ataxias, and Alzheimer's disease (AD). Type, frequency, and severity of sleep disturbances vary depending on each of these diseases. Cell loss of the brainstem nuclei that modulates respiration, and dysfunction of bulbar and diaphragmatic muscles increase the risk for sleep-disordered breathing (SDB) in MSA and ALS. The most relevant SDB in MSA is stridor, whereas in ALS nocturnal hypoventilation due to diaphragmatic weakness is the most common sleep breathing abnormality. Stridor and nocturnal hypoventilation are associated with reduced survival in MSA and ALS. In contrast, sleep apnea seems not to be more prevalent in PD than in the general population. In some PD patients, however, coincidental obstructive sleep apnea (OSA) can be the cause of excessive daytime sleepiness (EDS). SDB can also occur in some hereditary ataxias, such as stridor in spinocerebellar ataxia type 3 (Machado-Joseph disease). The presence of concomitant OSA in patients with AD can have deleterious effects on nocturnal sleep, may result in EDS, and might aggravate the cognitive deficits inherent to the disease. However, whether OSA is more frequent in patients with AD than in the general population is uncertain. Recognition of SDB in neurodegenerative disease is important because they are associated with significant morbidity and potential effective treatments are available. [ABSTRACT FROM AUTHOR]

Predictive testing protocols are intended to help patients affected with hereditary conditions understand their condition and make informed reproductive choices. However, predictive protocols may expose clinicians and patients to ethical dilemmas that interfere with genetic counseling and the decision making process. This paper describes ethical dilemmas in a series of five cases involving predictive testing for hereditary ataxias in Cuba. The examples herein present evidence of the deeply controversial situations faced by both individuals at risk and professionals in charge of these predictive studies, suggesting a need for expanded guidelines to address such complexities. [ABSTRACT FROM AUTHOR]

Objective: In this paper, we present a descriptive study of the first year of implementation of the predictive genetic testing program for spinocerebellar ataxia type 2 (SCA2) in Cuba, which has been structured along the international guidelines for Huntington disease. Subjects and Methods:Medical records were retrospectively reviewed from 100 individuals who requested presymptomatic diagnosis. They had been seen between February 2001 and May 2002 at the Ataxia Clinic in the province of Holguín and had completed the protocol. The participants had psychological evaluations before testing and 1 week after being informed of the result. Results: The average age of the participants in the presymptomatic testing for SCA2 was 39.3 years, 62% were female. The main reasons for taking the test were family planning and risk assessment in their children. Family participation in the process was high and there were several additional sources of social support. Before the test, the subjects did not present high levels of anxiety or depression. On informing the patients of the test results indicators for anxiety and depression significantly decreased, and there were no significant differences according to whether the test result had been positive or negative. Catastrophic events were rare during the first week after the test. Conclusions: The results indicate a strong interest in presymptomatic diagnosis among individuals at risk for SCA2 in Holguín and a lack of significant psychological drawbacks up to 1 week after information of results. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Machado–Joseph disease [MJD, also spinocerebellar ataxia type 3 (SCA3)] and familial amyloid polyneuropathy type I (FAP-I or ATTR V30M) are neurodegenerative disorders, inherited in an autosomal dominant fashion, which have a high prevalence in Portugal, probably due to a founder effect. MJD and FAP-I are late-onset diseases, with symptoms emerging usually during adulthood. CGPP, which is the national reference centre for these disorders, has a genetic lab that offers diagnostic, pre-symptomatic and prenatal testing and an outpatient clinic to counsel and follow relatives at risk for hereditary ataxias, FAP-I and Huntington disease (HD). The present work is a review of our 10-year experience with psychological counselling of individuals at risk for MJD and FAP-I. Persons at risk for FAP-I may show a better response to pre-symptomatic testing than those who are at risk for MJD and HD because of the availability of liver transplantation, which may improve their health and life expectancy. Psychological well-being and specific distress of MJD and FAP-I test applicants, before undergoing genetic testing (baseline level) and 3 to 6 months after disclosure of test results, have shown a low level of change, both in identified carriers and non-carriers. A major goal of psychological characterization of at-risk individuals for MJD and FAP-I is to determine the factors that influence the uptake of genetic testing. [ABSTRACT FROM AUTHOR]

Harding’s classification takes credits for defining the homogeneous phenotypes that have been essential for the genetic linkage studies and it is still useful for didactic purposes. The advances in pathogenetic knowledge make it now possible to modify Harding’s classification. Five main pathogenetic mechanisms may be distinguished: 1) mitochondrial; 2) metabolic; 3) defective DNA repair; 4) abnormal protein folding and degradation; 5) channelopathies. The present attempt to classify ataxia disorders according to their pathogenetic mechanism is a work in progress, since the pathogenesis of several disorders is still unknown. A pathogenetic classification may be useful in clinical practice and when new therapeutic strategies become available. [ABSTRACT FROM AUTHOR]