New THAP1 mutation and role of putative modifier in TOR1A.

OBJECTIVES: The prevalence of DYT1 (mutation in TOR1A) and DYT6 (mutation in THAP1) may vary in different populations, which can have important implications in clinical investigation. Our goal was to characterize patients with inherited and isolated dystonia and determine the frequency of mutations responsible for DYT1 and DYT6 in Brazilian patients. METHODS: Two movement disorder specialists examined 78 patients with idiopathic isolated dystonia using a standardized questionnaire, before sequencing TOR1A and THAP1 genes. RESULTS: Clinically, our cohort was similar to those described in the international literature. Molecular studies of 68 subjects revealed only one potentially deleterious variant in THAP1 (1/68 patients, 1.47%). This was a novel 10-bp deletion at the end of exon 1, g.5308_5317del (ng_011837.1), which is predicted to create an alternative splicing and the insertion of a premature stop codon. Although we did not observe any potentially deleterious mutations in TOR1A, we found the missense variant rs1801968 (TOR1A p.D216H), previously reported as either a modifier of dystonia phenotype or a predisposing factor for dystonia. However, we did not identify any phenotypic impact related to the missense variant rs1801968 (P = 0.3387). CONCLUSIONS: Although clinically similar to most cohorts with dystonia worldwide, the classical mutation (c.907_909delGAG) in TOR1A (causing DYT1) is absent in our patients. However, we found a potentially deleterious THAP1 mutation not previously reported. In addition, we found no association of rs1801968 with dystonia.

Non-motor symptoms in patients with hereditary spastic paraplegia caused by SPG4 mutations.

BACKGROUND AND PURPOSE: Non-motor manifestations are frequently overlooked in degenerative disorders and little is known about their frequency and clinical relevance in SPG4 hereditary spastic paraplegia (SPG4-HSP). METHODS: Thirty patients with SPG4-HSP and 30 healthy controls answered the Modified Fatigue Impact Scale, Epworth Sleepiness Scale, Brief Pain Inventory and Beck Depression Inventory. Student's t test was used to compare groups and linear regression was used to assess correlations. RESULTS: Patients had higher fatigue scores than controls (31.0 ± 16.5 vs. 14.5 ± 16.0, P = 0.002) as well as pain (3.4 ± 2.7 vs. 1.0 ± 1.6, P = 0.001) and depression (12.7 ± 8.9 vs. 4.4 ± 3.8, P < 0.001, respectively). Fatigue was associated with depression and possibly with disease severity (P = 0.008 and 0.07, respectively). CONCLUSIONS: Fatigue, pain and depression are frequent and often severe manifestations in patients with SPG4-HSP.

Cerebral cortex involvement in Machado-Joseph disease.

BACKGROUND AND PURPOSE: Machado-Joseph disease (MJD/SCA3) is the most frequent spinocerebellar ataxia, characterized by brainstem, basal ganglia and cerebellar damage. Few magnetic resonance imaging based studies have investigated damage in the cerebral cortex. The objective was to determine whether patients with MJD/SCA3 have cerebral cortex atrophy, to identify regions more susceptible to damage and to look for the clinical and neuropsychological correlates of such lesions. METHODS: Forty-nine patients with MJD/SCA3 (mean age 47.7 ± 13.0 years, 27 men) and 49 matched healthy controls were enrolled. All subjects underwent magnetic resonance imaging scans in a 3 T device, and three-dimensional T1 images were used for volumetric analyses. Measurement of cortical thickness and volume was performed using the FreeSurfer software. Groups were compared using ancova with age, gender and estimated intracranial volume as covariates, and a general linear model was used to assess correlations between atrophy and clinical variables. RESULTS: Mean CAG expansion, Scale for Assessment and Rating of Ataxia (SARA) score and age at onset were 72.1 ± 4.2, 14.7 ± 7.3 and 37.5 ± 12.5 years, respectively. The main findings were (i) bilateral paracentral cortex atrophy, as well as the caudal middle frontal gyrus, superior and transverse temporal gyri, and lateral occipital cortex in the left hemisphere and supramarginal gyrus in the right hemisphere; (ii) volumetric reduction of basal ganglia and hippocampi; (iii) a significant correlation between SARA and brainstem and precentral gyrus atrophy. Furthermore, some of the affected cortical regions showed significant correlations with neuropsychological data. CONCLUSIONS: Patients with MJD/SCA3 have widespread cortical and subcortical atrophy. These structural findings correlate with clinical manifestations of the disease, which support the concept that cognitive/motor impairment and cerebral damage are related in disease.

Dentate nuclei T2 relaxometry is a reliable neuroimaging marker in Friedreich's ataxia.

BACKGROUND AND PURPOSE: In Friedreich's ataxia (FRDA), frataxin deficiency results in iron redistribution in the dentate nuclei (DNC). Clusters of iron cause inhomogeneities in a magnetic field and result in a reduction in T2 relaxation time (T2). METHODS: T2 was prospectively evaluated in DNC, putamen, substantia nigra (SN), cerebellar white matter (CWM) and caudate and the correlation with clinical parameters was investigated. Thirty-five patients (range 9-51 years) and 44 controls (12-49 years) underwent T2 multi-echo sequence in a 3T scanner. Twenty-three patients (12-50 years) and 19 controls (14-49 years) were reassessed after 1 year. T2 was evaluated using specialized software (Aftervoxel) and severity of disease was quantified with the Friedreich Ataxia Rating Scale (FARS). RESULTS: T2 of both DNC was significantly shorter in the FRDA group at baseline (right, 58.6 ± 8.3 ms vs. 63.7 ± 8.1 ms, P = 0.013; left, 56.7 ± 7.7 ms vs. 62.6 ± 6.8 ms, P = 0.001). No significant difference was found between groups regarding the SN, putamen, CWM and caudate T2. DNC T2 values correlated with age, FARS total score and FARS III subscore on both sides. Prospectively, there was a significant reduction of T2 in FRDA patients in right and left DNC (P = 0.001 and 0.009) but not in other structures. Amongst controls, none of the regions significantly changed after 1 year. DNC T2 change over time correlated with GAA expansions and clinical deterioration (expressed by a change in FARS scores). CONCLUSIONS: DNC T2 values are abnormal in FRDA, progress over time and correlate with ataxia severity. These results strongly suggest that DNC relaxometry can be a useful neuroimaging marker in FRDA.

Thalamic metabolic abnormalities in patients with Huntington's disease measured by magnetic resonance spectroscopy.

Huntington's disease (HD) is a neurologic disorder that is not completely understood; its fundamental physiological mechanisms and chemical effects remain somewhat unclear. Among these uncertainties, we can highlight information about the concentrations of brain metabolites, which have been widely discussed. Concentration differences in affected, compared to healthy, individuals could lead to the development of useful tools for evaluating the progression of disease, or to the advance of investigations of different/alternative treatments. The aim of this study was to compare the thalamic concentration of metabolites in HD patients and healthy individuals using magnetic resonance spectroscopy. We used a 2.0-Tesla magnetic field, repetition time of 1500 ms, and echo time of 135 ms. Spectra from 40 adult HD patients and 26 control subjects were compared. Quantitative analysis was performed using the LCModel method. There were statistically significant differences between HD patients and controls in the concentrations of N-acetylaspartate+N-acetylaspartylglutamate (NAA+NAAG; t-test, P<0.001), and glycerophosphocholine+phosphocholine (GPC+PCh; t-test, P=0.001) relative to creatine+phosphocreatine (Cr+PCr). The NAA+NAAG/Cr+PCr ratio was decreased by 9% and GPC+PCh/Cr+PCr increased by 17% in patients compared with controls. There were no correlations between the concentration ratios and clinical features. Although these results could be caused by T1 and T2 changes, rather than variations in metabolite concentrations given the short repetition time and long echo time values used, our findings point to thalamic dysfunction, corroborating prior evidence.

Thalamic metabolic abnormalities in patients with Huntington's disease measured by magnetic resonance spectroscopy

Huntington's disease (HD) is a neurologic disorder that is not completely understood; its fundamental physiological mechanisms and chemical effects remain somewhat unclear. Among these uncertainties, we can highlight information about the concentrations of brain metabolites, which have been widely discussed. Concentration differences in affected, compared to healthy, individuals could lead to the development of useful tools for evaluating the progression of disease, or to the advance of investigations of different/alternative treatments. The aim of this study was to compare the thalamic concentration of metabolites in HD patients and healthy individuals using magnetic resonance spectroscopy. We used a 2.0-Tesla magnetic field, repetition time of 1500 ms, and echo time of 135 ms. Spectra from 40 adult HD patients and 26 control subjects were compared. Quantitative analysis was performed using the LCModel method. There were statistically significant differences between HD patients and controls in the concentrations of N-acetylaspartate+N-acetylaspartylglutamate (NAA+NAAG; t-test, P<0.001), and glycerophosphocholine+phosphocholine (GPC+PCh; t-test, P=0.001) relative to creatine+phosphocreatine (Cr+PCr). The NAA+NAAG/Cr+PCr ratio was decreased by 9% and GPC+PCh/Cr+PCr increased by 17% in patients compared with controls. There were no correlations between the concentration ratios and clinical features. Although these results could be caused by T1 and T2 changes, rather than variations in metabolite concentrations given the short repetition time and long echo time values used, our findings point to thalamic dysfunction, corroborating prior evidence.

Glucocerebrosidase gene variants in parkinsonian patients with Machado Joseph/spinocerebellar ataxia 3.

UNLABELLED: Machado-Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3) may rarely presents a parkinsonian phenotype. Considering that mutations in the glucocerebrosidase (GBA) gene have been associated with Parkinson disease, we investigated whether these would be more prevalent in MJD/SCA3 patients with parkinsonian manifestations than in those without them. METHODS: MJD/SCA3 patients with parkinsonian features were identified and compared to relatives and to a MJD/SCA3 control group with no such features. The GBA gene was sequenced and, in a subset of patients and in normal volunteers, GBA enzyme activity was measured. RESULTS: We have identified nine index MJD/SCA3 patients with parkinsonian manifestations. Overall, GBA sequence variations were found in 3/9 MJD/SCA3 index cases with parkinsonian manifestations (33%) and in 0/40 MJD/SCA3 controls without parkinsonism (p=0.03, Fisher exact test). The GBA sequence variations found were p.K(-27)R, p.E326K, and p.T369M. The latter two sequence variations were also found in two symptomatic relatives with no parkinsonian manifestations. A MJD/SCA3 relative belonging to the first positive pedigree and carrier of the p.K(-27)R mutation also presented parkinsonian manifestations. GBA activity in MJD/SCA3 patients was similar to those found in the normal control group. CONCLUSION: Sequence variations at the GBA gene may play a role as a minor, modifying gene of MJD/SCA3 phenotype. This hypothetical role was not related to changes in GBA activity in peripheral leukocytes.

MR imaging texture analysis of the corpus callosum and thalamus in amnestic mild cognitive impairment and mild Alzheimer disease.

BACKGROUND AND PURPOSE: TA is a branch of image processing that seeks to reduce image information by extracting texture descriptors from the image. TA of MR images of anatomic structures in mild AD and aMCI is not well-studied. Our objective was to attempt to find differences among patients with aMCI and mild AD and normal-aging subjects, by using TA applied to the MR images of the CC and the thalami of these groups of subjects. MATERIALS AND METHODS: TA was applied to the MR images of 17 patients with aMCI, 16 patients with mild AD, and 16 normal-aging subjects. The TA approach was based on the GLCM. MR images were T1-weighted and were obtained in the sagittal and axial planes. The CC and thalami were manually segmented for each subject, and 44 texture parameters were computed for each of these structures. RESULTS: TA parameters showed differences among the 3 groups for the CC and thalamus. A pair-wise comparison among groups showed differences for AD-control and aMCI-AD for the CC; and for AD-control, aMCI-AD, and aMCI-control for the thalamus. CONCLUSIONS: TA is a useful technique to aid in the detection of tissue alterations in MR images of mild AD and aMCI and has the potential to become a helpful tool in the diagnosis and understanding of these pathologies.

Clinical correlates of autonomic dysfunction in patients with Machado-Joseph disease.

BACKGROUND: Autonomic dysfunction is a usual feature of several neurological conditions characterized by either extra-pyramidal and/or peripheral damage, such as those seen in Machado-Joseph disease (MJD). AIMS OF THE STUDY: We used clinical evaluation and sympathetic skin responses (SSR) to assess autonomic function in a large series of patients with MJD. METHODS: A total of 50 patients were enrolled in this study and all of them had the molecular confirmation of MJD by DNA genotyping. In addition, a group of 20 control subjects was included. RESULTS: Overall, autonomic complaints were more frequent in patients than in control subjects, especially those related to the genitourinary and sudomotor systems. Eighteen patients (36%) presented abnormal SSR. Age at onset, duration of disease and length of expanded (CAG)(n) were not different between patients with and without dysautonomia. However, severe dysautonomia was significantly associated with polyneuropathic or parkinsonian phenotypes in patients with MJD. CONCLUSION: Autonomic symptoms are common, but possibly under recognized in patients with MJD; therefore, we believe that autonomic complaints should be sought in patients with MJD, especially in those with parkinsonian or polyneuropathic phenotypes.

Sleep symptoms and their clinical correlates in Machado-Joseph disease.

OBJECTIVE: To evaluate the presence of sleep symptoms in Machado-Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3). SUBJECTS/METHODS: We used a sleep questionnaire and the Epworth Sleepiness Scale to compare 53 patients with MJD/SCA3 and 106 controls. RESULTS: Patients with MJD/SCA3 reported more symptoms of insomnia, restless leg syndrome and REM sleep behavior disorder as well as nocturnal cramps, snoring and nocturnal apnea. Insomnia was the most frequently reported sleep-related complaint in the MJD/SCA3 group. CONCLUSIONS: Our results indicate that sleep disorders are common in patients with MJD/SCA3 and probably have a multifactorial etiology, with components of a primary sleep disorder in addition to sleep-disrupting symptoms such as nocturia and cramps.

Excessive daytime sleepiness and on-road driving performance in patients with Parkinson's disease.

The impact of excessive daytime sleepiness (EDS) on road test performance was examined in patients with Parkinson's disease (PD). Twenty-one patients with PD completed the Epworth Sleepiness Scale (ESS) and an on-road driving test. Five participants had EDS according to their self-report on the ESS. Neither EDS nor PD medications were associated with on-road driving performance. These findings suggest that in this pilot study EDS did not impair PD patients' driving skills on a formal driving evaluation.

Histopathological changes in avian kidney caused by Bothrops insularis (jararaca ilh a) venom and a phospholipase A2-containing fraction.

The histopathological changes induced in avian kidney by the intramuscular injection of Bothrops insularis (jararaca ilh a) venom and its phospholipase A2 (PLA2)-containing fraction were examined. Acute experiments (3 h and 24 h) with B. insularis crude venom (20 microg and 80 microg) or its PLA2-contaning fraction (10 microg and 40 microg) resulted in significant structural damage to the kidneys of 5-12-day-old chicks. Histopathological analysis indicated that the venom and its fraction acted on the renal tubules and glomeruli. The morphological changes, although widespread, varied in intensity from cell to cell, and from tubule to tubule in venom-injected chicks. The tubular and glomerular changes produced by the venom and its PLA2-containing fraction may be the result of a direct cytotoxic effect potentiated by ischemia-related disturbances in the regional hemodynamics. The venom and its fraction affected more segments along reptilian-type nephrons than along mammalian ones. This divergent sensitivity to the venom and its fraction may reflect the species-specific characteristics of B. insularis snake, an example of geographical isolation influencing its diet which is almost exclusively avian.

[Interchange of babies in Portugal by exclusions in the ADA, GPT, ESD and HLA systems (author's transl)]. / Kindesvertauschung in Portugal durch Ausschlüsse im ADA-, GPT-, EsD- und HLA-System aufgeklärt.

The suspicion of an interchange of babies in two Portuguese families could not be dissipated in the first course of testing the following systems being considered: AB0, MNSs, Rhesus, Kell, Cellano, Duffy. Including further markers in an additional opinion, multiple father- and mother-exclusions could be made in the systems of ADA, GPT, EsD, and HLA. The suspicion thus showed to be justified and the children were given back to their natural parents.