Jonas Alex Morales Saute

Ataxia Rating Scales—Psychometric Profiles, Natural History and Their Application in Clinical Trials

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.

Nonmotor and extracerebellar features in Machado-Joseph disease: a review.

Spinocerebellar ataxia type 3 or Machado‐Joseph disease is the most common spinocerebellar ataxia worldwide, and the high frequency of nonmotor manifestations in Machado‐Joseph disease demonstrates how variable is the clinical expression of this single genetic entity. Anatomical, physiological, clinical, and functional neuroimaging data reinforce the idea of a degenerative process involving extracerebellar regions of the nervous system in Machado‐Joseph disease. Brain imaging and neuropathologic studies have revealed atrophy of the pons, basal ganglia, midbrain, medulla oblongata, multiple cranial nerve nuclei, and thalamus and of the frontal, parietal, temporal, occipital, and limbic lobes. This review provides relevant information about nonmotor manifestations and extracerebellar symptoms in Machado‐Joseph disease. The main nonmotor manifestations of Machado‐Joseph disease described in previous data and discussed in this article are: sleep disorders, cognitive and affective disturbances, psychiatric symptoms, olfactory dysfunction, peripheral neuropathy, pain, cramps, fatigue, nutritional problems, and dysautonomia. In addition, we conducted a brief discussion of noncerebellar motor manifestations, highlighting movement disorders.

A neurological examination score for the assessment of spinocerebellar ataxia 3 (SCA3)

Spinocerebellar ataxias (SCAs) are characterized by a heterogeneous set of clinical manifestations. Our aims were to assess the neurological features of SCA3, and to describe and test the feasibility, reliability, and validity of a comprehensive Neurological Examination Score for Spinocerebellar Ataxia (NESSCA). The NESSCA was administered to molecularly diagnosed SCA3 patients at an outpatient neurogenetics clinic. The scale, based on the standardized neurological examination, consisted of 18 items that yielded a total score ranging from 0 to 40. The score’s interrater reliability and internal consistency were investigated, and a principal components analysis and a correlation with external measures were performed. Ninety‐nine individuals were evaluated. Interrater reliability ranged from 0.8 to 1 across individual items (P < 0.001); internal consistency, indicated by Cronbach’s alpha, was 0.77. NESSCA scores were significantly correlated with measures of disease severity: disease stage (rho = 0.76, P < 0.001), duration (rho = 0.56, P < 0.001), and length of CAG repeat (rho = 0.30, P < 0.05). NESSCA was a reliable measure for the assessment of distinct neurological deficits in SCA3 patients. Global scores correlated with all external variables tested, showing NESSCA to be a comprehensive measure of disease severity that is both clinically useful and scientifically valid.

DNAJC6 Mutations Associated with Early-Onset Parkinson's Disease

DNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age < 11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair‐bound within ∼10 years from onset). Here, for the first time, we report DNAJC6 mutations in early‐onset Parkinsons disease (PD).

A Randomized, Phase 2 Clinical Trial of Lithium Carbonate in Machado-Joseph Disease

Because lithium exerts neuroprotective effects in preclinical models of polyglutamine disorders, our objective was to assess the safety and efficacy of lithium carbonate (0.5‐0.8 milliequivalents per liter) in patients with Machado‐Joseph disease (spinocerebellar ataxia type 3 [MJD/SCA3]).

Evidence that folic acid deficiency is a major determinant of hyperhomocysteinemia in Parkinson´s disease

In the present work we measured blood levels of total homocysteine (tHcy), vitamin B12 and folic acid in patients with Parkinson´s disease (PD) and in age-matched controls and searched for possible associations between these levels with smoking, alcohol consumption, L-DOPA treatment and disease duration in PD patients. We initially observed that plasma tHcy levels were increased by around 30 % in patients affected by PD compared to controls. Linear correlation, multiple regression and comparative analyses revealed that the major determinant of the increased plasma concentrations of tHcy in PD patients was folic acid deficiency, whereas in controls tHcy levels were mainly determined by plasma vitamin B12 concentrations. We also observed that alcohol consumption, gender and L-DOPA treatment did not significantly alter plasma tHcy, folic acid and vitamin B12 levels in parkinsonians. Furthermore, disease duration was positively associated with tHcy levels and smoking was linked with a deficit of folic acid in PD patients. Considering the potential synergistic deleterious effects of Hcy increase and folate deficiency on the central nervous system, we postulate that folic acid should be supplemented to patients affected by PD in order to normalize blood Hcy and folate levels, therefore potentially avoiding these risk factors for neurologic deterioration in this disorder.

Body mass index is inversely correlated with the expanded CAG repeat length in SCA3/MJD patients.

Spinocerebellar ataxia type 3, also known as Machado–Joseph disease (SCA3/MJD), is an autosomal dominant neurodegenerative disorder with no current treatment. We aimed to evaluate the body mass index (BMI) of patients with SCA3/MJD and to assess the correlations with clinical, molecular, biochemical, and neuroimaging findings. A case–control study with 46 SCA3/MJD patients and 42 healthy, non-related control individuals with similar age and sex was performed. Clinical evaluation was done with the ataxia scales SARA and NESSCA. Serum insulin, insulin-like growth factor 1 (IGF-1) and magnetic resonance imaging normalized volumetries of cerebellum and brain stem were also assessed. BMI was lower in SCA3/MJD patients when compared to controls (p = 0.01). BMI was associated with NESSCA, expanded CAG repeat number (CAG)n, age of onset, age, disease duration, and serum insulin levels; however, in the linear regression model, (CAG)n was the only variable independently associated with BMI, in an inverse manner (R = −0.396, p = 0.015). In this report, we present evidence that low BMI is not only present in SCA3/MJD, but is also directly related to the length of the expanded CAG repeats, which is the causative mutation of the disease. This association points that weight loss might be a primary disturbance of SCA3/MJD, although further detailed analyses are necessary for a better understanding of the nutritional deficit and its role in the pathophysiology of SCA3/MJD.

Spinocerebellar ataxias in 114 Brazilian families: clinical and molecular findings.

To the Editor: Dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases that affect the cerebellum, brain stem, and spinocerebellar tracts. SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17 and dentatorubral pallidoluysian atrophy (DRPLA) are caused by CAG trinucleotide repeat expansions (1). SCA8 has a CTG expansion in the causative gene. SCA10 has been found to represent a large expansion of a pentanucleotide (ATTCT) repeat (2). The frequency of each SCA varies between regions and ethnic groups. Machado–Joseph disease (MJD/SCA3) is the most common SCA among populations with Portuguese and Azorean background and populations in Japan and Germany (3–10). SCA2 is common in Cuba, India, Korea, and Italy (11– 14). SCA10 has been only described in the New World (15–19). Our aim was to determine the frequency of the SCA1, SCA2, SCA3, SCA6, SCA7, SCA10, SCA17 and DRPLA among SCA families who have the same geographic origin, namely southern Brazil (Rio Grande do Sul). Clinical, epidemiological, and molecular features are also described herein. Cases were recruited based on the following inclusion criteria: (1) ataxia, often associated with other neurological signs; and (2) inheritance as an autosomal dominant trait. Neurological examination followed a standard examination already published (19). Presence and gradation of several neurological findings were evaluated as numeric ordinal variables. Peripheral blood was collected, and genomic DNA was isolated from peripheral blood leukocytes, using the salting-out technique, as previously described (20). Molecular analyses of the repeat loci were performed by molecular tests specific to each ataxia by PCR amplification. Southern blot was performed to SCA10 locus. Patients were stratified according to their molecular diagnosis. Clinical variables were then compared between these groups. Comparisons were performed using analysis of variance (ANOVA), when the variable was parametric, or the Kruskal–Wallis test (KW test), when the variable was nonparametric. A Bonferroni procedure was done, in order to correct for multiple testing. This study was approved by the ethics committee of the institution where it was conducted; informed consent forms were filled out by all patients. A total of 114 families with autosomal dominant trait were investigated during an 8-year period (up to 2004). Diagnosis, ethnicity, and main clinical features are presented in Tables 1 and 2. SCA3 was the most prevalent, comprising 84.2% of all SCAs. The other SCAs were far less common and represented from one to five pedigrees each. The number of clinically examined patients with the diverse molecular diagnoses was variable. Due to this, some statistical comparisons could not be done: SCA1 and SCA10 patients were excluded from comparisons. Neurological findings that showed statistical differences among groups were (1) nystagmus, less frequent in cases with SCA2 and SCA7 than in the general sample; (2) limb ataxia, more severe in SCA6 patients; and (3) pyramidal findings and optic atrophy, more common in SCA7 patients than in other groups (p , 0.0025, 0.0025, 0.041 and 0.0411, respectively; KW test). Most of the present families were of mixed ancestry but Portuguese surnames prevailed. In our region, the main Portuguese ancestry was Azorean in origin, dating from circa 1750 (7). The Amerindians are another important ancestry. The composition of mitochondrial Amerindian markers in urban Brazilian populations is high and varies between 22% and 54% (26). This finding shows the importance of this Brazilian ancestry. So far, SCA10 has only been described in American families (15–18, 27). The finding of two SCA10 kindreds is in line with the hypothesis that this mutation is somehow restricted to patients with an Amerindian ancestry. Although some of the present families have already been described (7, 18, 19, 28), they had never been compared. We made these comparisons

Machado Joseph disease: clinical and genetic aspects, and current treatment

Introduction: Spinocerebellar ataxia (SCA) type 3/Machado–Joseph disease (SCA3/MJD) is the most common SCA worldwide. SCA3/MJD is an adult onset cerebellar ataxia associated with pyramidal, lower motor neuron and extrapyramidal findings, resulting in heterogeneous phenotypic presentations. SCA3/MJD is caused by a CAG repeat expansion at the ATXN3 gene that codes for ataxin-3. Mutant ataxin-3 trigger multiple, interconnected pathogenic cascades, but many of key disease mechanisms remain unclear. Areas covered: This review focused on the present knowledge about the genetic characteristics, ancestral origins, selective forces, clinical course and determinants of phenotypic heterogeneity of SCA3/MJD. Disease-modifying and symptomatic therapies were also detailed. Expert opinion: Although no evidence exists for disease-modifying therapies for SCA3/MJD, symptomatic treatments for some disease signs are available. Genetic counseling is fundamental and should include discussion on options such as prenatal or pre-implantation diagnoses, and adoption, as ways to prevent the disease. Basic and translational science trying to speed the exchange of novel therapies (e.g., gene silencing) to the clinics will be central to the development of effective therapies, together with consortiums to define surrogate disease biomarkers and essential data for planning future clinical trials on SCA3/MJD.

Huntington disease and Huntington disease-like in a case series from Brazil

The aim of this study was to identify the relative frequency of Huntingtons disease (HD) and HD‐like (HDL) disorders HDL1, HDL2, spinocerebellar ataxia type 2 (SCA2), SCA17, dentatorubral‐pallidoluysian degeneration (DRPLA), benign hereditary chorea, neuroferritinopathy and chorea‐acanthocytosis (CHAC), in a series of Brazilian families. Patients were recruited in seven centers if they or their relatives presented at least chorea, besides other findings. Molecular studies of HTT, ATXN2, TBP, ATN1, JPH3, FTL, NKX2‐1/TITF1 and VPS13A genes were performed. A total of 104 families were ascertained from 2001 to 2012: 71 families from South, 25 from Southeast and 8 from Northeast Brazil. There were 93 HD, 4 HDL2 and 1 SCA2 families. Eleven of 104 index cases did not have a family history: 10 with HD. Clinical characteristics were similar between HD and non‐HD cases. In HD, the median expanded (CAG)n (range) was 44 (40–81) units; R2 between expanded HTT and age‐at‐onset (AO) was 0.55 (p = 0.0001, Pearson). HDL2 was found in Rio de Janeiro (2 of 9 families) and Rio Grande do Sul states (2 of 68 families). We detected HD in 89.4%, HDL2 in 3.8% and SCA2 in 1% of 104 Brazilian families. There were no cases of HDL1, SCA17, DRPLA, neuroferritinopathy, benign hereditary chorea or CHAC. Only six families (5.8%) remained without diagnosis.