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Friedreich's Ataxia (FRDA) is the leading cause of ataxia worldwide, but data on epidemiology and diagnostic journey are scarce, particularly in Latin America. Herein we estimated the prevalence of FRDA in the most populous Brazilian state and characterized the diagnostic odyssey of the disease. We received anonymized data of patients with FRDA from advocacy groups and physicians. Prevalence was estimated dividing the number of patients by the population of the state as reported in the last census. Patients were invited to answer an online survey to describe clinical data and diagnostic journey of the disease. FRDA estimated prevalence was 0.367:100,000, with a slight predominance of women (58.2% vs 41.7%). One hundred and four patients answered the survey (mean age of 37.3 ± 13.8 years; 75.9% classical and 24.0% late onset). On average, 6.2 ± 4.1 physicians were visited before reaching the diagnosis. Mean diagnostic delay was 7.8 ± 6.7 years; no difference between classical and LOFA groups was found. Most of the patients reported unsteadiness and gait abnormalities as the first symptom. Neurologists and orthopedical surgeons were the main specialties first sought by patients. We found a prevalence of 0.36:100,000 for FRDA in the state of São Paulo, Brazil. The disease is characterized by remarkable diagnostic delay, with no relevant differences between classical and LOFA patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cerebellar cognitive affective syndrome (CCAS) is characterized by deficits in executive functions, language processing, spatial orientation, and affect regulation in patients with cerebellar disease. The symptoms can occur isolated or along with motor and coordination symptoms. The aim of our study was to translate and culturally adapt the CCAS scale to Brazilian Portuguese and validate the scale in our population. We performed a cross-sectional study with patients with primary and secondary ataxia. The study included 111 individuals, aged between 20 and 80 years, of both genders, 20 without cognitive and/or affective complaints who participated in the pre-test phase, 40 with cerebellar disease (hereditary/neurodegenerative ataxia or acquired/secondary cerebellar ataxia), and 51 healthy controls with no evidence of cognitive impairment and no affective symptoms matched for sex, age, and educational level. The scale was translated, culturally adapted, and validated. Statistical analysis of the data was performed, with association tests, mean comparison, and ROC curve analysis. Based on the analysis of the ROC curve, optimal cutoff values ​were found for each subitem of the scale. The translated and adapted scale has good internal consistency, is reproducible, has good reliability, and has the potential to be a reliable tool for screening cognitive symptoms in patients with cerebellar disease., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Spastic ataxia is characterized by the combination of cerebellar ataxia with spasticity and other pyramidal features. It is the hallmark of some hereditary ataxias, but it can also occur in some spastic paraplegias and acquired conditions. It often presents with heterogenous clinical features with other neurologic and non-neurological symptoms, resulting in complex phenotypes. In this review, the differential diagnosis of spastic ataxias are discussed and classified in accordance with inheritance. Establishing an organized classification method based on mode inheritance is fundamental for the approach to patients with these syndromes. For each differential, the clinical features, neuroimaging and genetic aspects are reviewed. A diagnostic approach for spastic ataxias is then proposed., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neuropathy is a common associated feature of different types of genetic or sporadic cerebellar ataxias. The pattern of peripheral nerve involvement and its associated clinical features can be an invaluable aspect for narrowing the etiologic diagnosis in the investigation of cerebellar ataxias. In this review, we discuss the differential diagnosis of the intersection between peripheral nerve and cerebellar involvement, and classify them in accordance with the predominant features. Genetics, clinical features, neuroimaging, and neurophysiologic characteristics are discussed. Furthermore, a diagnostic approach for cerebellar ataxia with neuropathy is proposed according to the different clinical characteristics. This is an Educational and Descriptive review with the aim of medical education for the approach to the patients with cerebellar ataxia and neuropathy. The diagnostic approach to the patient with cerebellar ataxia with neuropathy requires a detailed medical history, phenotyping, characterization of disease progression and family history. Neuroimaging features and the neurophysiological findings play pivotal roles in defining the diagnosis. Establishing an organized classification method for the disorders based on the clinical features may be very helpful, and could be divided as those with predominant cerebellar features, predominant neuropathic feature, or conditions with both cerebellar ataxia and neuropathy. Second, determining the mode of inheritance is critical on cerebellar ataxias: autosomal dominant and recessive cerebellar ataxias, mitochondrial or sporadic types. Third, one must carefully assess neurophysiologic findings in order to better characterize the predominant pattern of involvement: damage location, mechanism of lesion (axonal or demyelinating), motor, sensory or sensory motor compromise, large or small fibers, and autonomic system abnormalities., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Niemann-Pick type C (NPC) is a rare autosomal recessive disorder characterized by storage of unesterified glycolipids and cholesterol in lysosome. NPC's clinical presentation is highly heterogeneous, depending on the time of onset. It encompasses visceral, neurological, and/or psychiatric manifestations. As the motor findings are so important and devastating in this disease, there is a lack of description about non-motor symptoms, even though they play important role in quality of life of NPC patients. We described the most common non-motor findings in NPC like cognitive dysfunction, neuroimaging, psychiatric symptoms, sleep disorders, seizures, hearing problems, respiratory and other systemic features, bladder and fecal dysfunction, hypersalivation, and malnutrition. In this review, we highlighted the importance of these undervalued symptoms and their management. Specific measures of all aforementioned clinical features may work as relevant biomarkers in order to evaluate successful therapies in future clinical trials.

Machado-Joseph disease (MJD) is the most common spinocerebellar ataxia worldwide with a broad range of clinical manifestations, but psychotic symptoms were not previously characterized. We investigated the psychiatric manifestations of a large cohort of Brazilian patients with MJD in an attempt to characterize the presence of psychotic symptoms. We evaluated 112 patients with clinical and molecular diagnosis of MJD from February 2008 to November 2013. Patients with psychotic symptoms were referred to psychiatric evaluation and brain perfusion single-photon emission computed tomography (SPECT) analysis. A specific scale-Positive and Negative Syndrome Scale (PANSS)-was used to characterize psychotic symptoms in MJD patients. We also performed an autopsy from one of the patients with MJD and psychotic symptoms. Five patients presented psychotic symptoms. Patients with psychotic symptoms were older and had a late onset of the disease (p < 0.05). SPECT results showed that MJD patients had significant regional cerebral blood flow (rCBF) decrease in the cerebellum bilaterally and vermis compared with healthy subjects. No significant rCBF differences were found in patients without psychotic symptoms compared to patients with psychotic symptoms. The pathological description of a patient with MJD and psychotic symptoms revealed severe loss of neuron bodies in the dentate nucleus and substantia nigra. MJD patients with a late onset of the disease and older ones are at risk to develop psychotic symptoms during the disease progression. These clinical findings may be markers for an underlying cortical-cerebellar disconnection or degeneration of specific cortical and subcortical regions that may characterize the cerebellar cognitive affective syndrome.

Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia characterized by a combination of neurological involvement, cardiomyopathy, and skeletal and glucose metabolism disturbances. FRDA is caused by mutations in FXN gene that results in reduction of mRNA and protein levels of frataxin. Previous microarray and real-time quantitative PCR (qPCR) studies showed that the downregulation of FXN is associated with a complex gene expression profile. However, these studies showed a wide variability in the subset of genes with altered expression among tissues and models. Genes differentially expressed in peripheral blood cells (PBC) could potentially help in the understanding of FRDA pathophysiology and also function as reliable disease biomarkers obtained from an easily accessible tissue, which could have implications in clinical practice. This study aimed to validate by qPCR the expression of 26 genes, revealed as differentially expressed by other studies, using peripheral blood cells (PBC) of 11 FRDA patients compared to 11 healthy controls. We found a robust downregulation of FXN, but no statistically significant differences were found between FRDA and controls for the remaining genes. Except for FXN, our study did not find a differential gene expression profile in PBC of FRDA patients and a reliable gene expression profile biomarker in a clinical relevant and noninvasive tissue remains unclear.

Spinocerebellar ataxia type 3 or Machado-Joseph disease is the most common spinocerebellar ataxia. In this neurological disease, anatomical, physiological, clinical, and functional neuroimaging demonstrate a degenerative process besides the cerebellum. We performed neurophysiological and neuroimaging studies-polysomnography, transcranial sonography, vestibular-evoked myogenic potential, single-photon emission computed tomography (SPECT) with (99m)Tc-TRODAT-1, and a formal neuropsychological evaluation in a patient with sleep complaints and positive testing for Machado-Joseph disease, without cerebellar atrophy, ataxia, or cognitive complaints. Polysomnography disclosed paradoxical high amplitude of submental muscle, characterizing REM sleep without atonia phenomenon. Transcranial sonography showed hyperechogenicity of the substantia nigra. There was an absence of vestibular-evoked myogenic potentials on both sides in the patient under study, in opposite to 20 healthy subjects. Brain imaging SPECT with (99m)Tc-TRODAT-1 demonstrated a significant lower DAT density than the average observed in six healthy controls. Electroneuromyography was normal. Neuropsychological evaluation demonstrated visuospatial and memory deficits. Impairment of midbrain cholinergic and pontine noradrenergic systems, dysfunction of the pre-synaptic nigrostriatal system, changes in echogenicity of the substantia nigra, and damage to vestibulo-cervical pathways are supposed to occur previous to cerebellar involvement in Machado-Joseph disease.

Cognitive and olfactory impairments have previously been demonstrated in patients with spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD)-SCA3/MJD. We investigated changes in regional cerebral blood flow (rCBF) using single-photon emission computed tomography (SPECT) imaging in a cohort of Brazilian patients with SCA3/MJD. The aim of the present study was to evaluate the correlation among rCBF, cognitive deficits, and olfactory dysfunction in SCA3/MJD. Twenty-nine genetically confirmed SCA3/MJD patients and 25 control subjects were enrolled in the study. The severity of cerebellar symptoms was measured using the International Cooperative Ataxia Rating Scale and the Scale for the Assessment and Rating of Ataxia. Psychiatric symptoms were evaluated by the Hamilton Anxiety Scale and Beck Depression Inventory. The neuropsychological assessment consisted of Spatial Span, Symbol Search, Picture Completion, the Stroop Color Word Test, Trail Making Test (TMT), and Phonemic Verbal Fluency. Subjects were also submitted to odor identification evaluation using the 16-item Sniffin' Sticks. SPECT was performed using ethyl cysteine dimer labeled with technetium-99m. SCA3/MJD patients showed reduced brain perfusion in the cerebellum, temporal, limbic, and occipital lobes compared to control subjects (pFDR <0.001). A significant positive correlation was found between the Picture Completion test and perfusion of the left parahippocampal gyrus and basal ganglia in the patient group as well as a negative correlation between the TMT part A and bilateral thalamus perfusion. The visuospatial system is affected in patients with SCA3/MJD and may be responsible for the cognitive deficits seen in this disease.

The cerebellum is no longer considered a purely motor control device, and convincing evidence has demonstrated its relationship to cognitive and emotional neural circuits. The aims of the present study were to establish the core cognitive features in our patient population and to determine the presence of Cerebellar Cognitive Affective Syndrome (CCAS) in this group. We recruited 38 patients with spinocerebellar ataxia type 3 (SCA3) or Machado–Joseph disease (MJD)-SCA3/MJD and 31 controls. Data on disease status were recorded (disease duration, age, age at onset, ataxia severity, and CAG repeat length). The severity of cerebellar symptoms was measured using the International Cooperative Ataxia Rating Scale and the Scale for the Assessment and Rating of Ataxia. The neuropsychological assessment consisted of the Mini-Mental State Examination, Clock Drawing Test, Wechsler Adult Intelligence Scale, Rey–Osterrieth Complex Figure, Wisconsin Card Sorting Test, Stroop Color–Word Test, Trail-Making Test, Verbal Paired Associates, and verbal fluency tests. All subjects were also submitted to the Hamilton Anxiety Scale and Beck Depression Inventory. After controlling for multiple comparisons, spatial span, picture completion, symbol search, Stroop Color–Word Test, phonemic verbal fluency, and Trail-Making Tests A and B were significantly more impaired in patients with SCA3/MJD than in controls. Executive and visuospatial functions are impaired in patients with SCA3/MJD, consistent with the symptoms reported in the CCAS. We speculate on a possible role in visual cortical processing degeneration and executive dysfunction in our patients as a model to explain their main cognitive deficit.

Sleep disorders are common complaints in patients with neurodegenerative diseases such as spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease (MJD)--SCA3/MJD. We evaluated the frequency of sleep disorders in SCA3/MJD patients against controls matched by age and gender, and correlated data with demographic and clinical variables. The main sleep disorders evaluated were rapid eye movement (REM) sleep behavior disorder (RBD), restless leg syndrome (RLS), and excessive daytime sleepiness (EDS). We recruited 40 patients with clinical and molecular-proven SCA3/MJD and 38 controls. We used the following clinical scales to evaluate our primary outcome measures: RBD Screening Questionnaire, International RLS Rating Scale, and Epworth Sleepiness Scale. To evaluate ataxia-related motor and non-motor features, we applied the International Cooperative Ataxia Rating Scale, the Scale for the Assessment and Rating of Ataxia, and the Unified Parkinson's Disease Rating Scale part III. Psychiatric manifestations were tested with the Hamilton Anxiety Scale, and Beck Depression Inventory. The frequency of RBD and RLS were significantly higher in the SCA3/MJD group than in the control group (p < 0.001). There was no difference between both groups with regard to EDS. The accuracy of RDBSQ to discriminate between cases and controls was considered the best area under the ROC curve (0.86). Within-SCA3/MJD group analysis showed that anxiety and depression were significantly correlated with RDB, but not with RLS. Additionally, depression was considered the best predictive clinical feature for RDB and EDS.