A large Japanese family with Machado-Joseph disease: clinical and genetic studies

A large Japanese family with probable Machado-Joseph disease (MJD) is described. Detailed neurological examination in 12 patients from 3 generations revealed variable combinations of cerebellar ataxia, ocular paresis, difficulty in eye-lid opening, bulging eyes, facial "myokymia", facial dystonia, pyramidal signs, extrapyramidal signs, and peripheral neuropathy. Mode of inheritance was in all likelihood autosomal dominant. Blood components were typed for 19 conventional chromosome markers. Although association of the affected members with the PGM1 system was high, linkage analysis failed to reveal any markers studied with a lod score higher than 3. The unique constellation of symptoms appeared sufficient to rule out other types of spinocerebellar degeneration. When there is a typical case in a given family, MJD appears to be a clinically recognizable entity.     

SCA2 in the Indian population: Unified haplotype and variable phenotypic patterns in a large case series

BackgroundSpinocerebellar ataxia-2 is one of the most prevalent SCA type across the world and one of the commonest in India. We aimed to characterize SCA2 patients both clinically and genetically (ATXN2-CAG repeats and its haplotypic background).MethodsA total of 436 SCA2 patients were recruited consecutively comprising individuals of multiple ethnicities and two large multigenerational families. A detailed clinical evaluation and genetic analysis for CAG repeat length estimation and two marker based haplotype analysis [rs695871 and rs695872 located 177 bp and 106 bp upstream of CAG sequence in Exon 1 of ATXN2] was performed.ResultsGeneralized limb ataxia and slow saccades were prevalent features in majority of our patients, while hyporeflexia and extrapyramidal features were less commonly observed manifestations. Slow ocular saccades, upper limb ataxia and tremor showed significant associations with age of onset, CAG repeat length and disease duration. We observed a 100% association of C-C haplotype with the expanded ATXN2 repeats.ConclusionThis study represents the largest study of SCA2 Indian patients that highlights the clinico-genetic manifestations and haplotype analysis. A significant proportion of patients have not shown the characteristic slow saccades and hyporeflexia thus indicating the influences of other factors in modulation of the disease which warrants further investigations. The observation of CC haplotype in all our SCA2 patients indicates a common origin across all Indian sub populations and that also indicate a common global founder event in the past.     

Depression,anxiety, and apathy in Parkinson's disease: insights from neuroimaging studies

Depression, anxiety and apathy are common mood disturbances in Parkinson's disease (PD) but their pathophysiology is unclear. Advanced neuroimaging has been increasingly used to unravel neural substrates linked to these disturbances. A systematic review is provided of neuroimaging findings in depression, anxiety and apathy in PD. A PubMed, MEDLINE and EMBASE search of peer‐reviewed original research articles on these mood disturbances in PD identified 38 studies on depression, eight on anxiety and 14 on apathy in PD. Most of the imaging studies used either position emission tomography or single‐photon emission computed tomography techniques. These studies generally suggest increased neural activity in the prefrontal regions and decreased functional connectivity between the prefrontal?limbic networks in depressed patients. Functional imaging studies revealed an inverse correlation between dopaminergic density in the caudate and putamen with the severity of anxiety in PD. There was no consistent correlation between dopaminergic density of thalamus and anxiety. Studies demonstrated both positive and inverse correlations between apathy and metabolism or activity in the striatum, amygdalar, prefrontal, temporal and parietal regions. The clinical variability of study subjects and differences in image pre‐processing and analytical strategies may contribute to discrepant findings in these studies. Both nigrostriatal and extra‐nigrostriatal pathways (in particular the frontal region and its connecting areas) are affected in mood disorders in PD. Identifying the relative contributions of these neural pathways in PD patients with overlapping motor and mood symptoms could provide new pathophysiological clues for the development of better therapeutic targets for affected patients.     

Machado-Joseph disease in New England: clinical description and distinction from the olivopontocerebellar atrophies.

Experience is described in 25 patients from southern New England with Machado-Joseph Disease, examined serially at annual screening clinics. The disorder is dominantly inherited, with a wide range of phenotypic variation. Core clinical features described include ataxia, nystagmus, dysarthria, facial fasciculations, and lid retraction, producing a characteristic staring expression. In addition, young onset patients have spasticity, extrapyramidal rigidity, and dystonic manifestations. Late onset patients often have distal atrophy and sensory loss. Postural instability is often an early feature. We discuss the distinction of this entity from the olivopontocerebellar atrophies.     

Asian origin for the worldwide-spread mutational event in Machado-Joseph disease

BACKGROUND: Machado-Joseph disease is the most frequent dominant ataxia worldwide. Despite its frequency and presence in many populations, only 2 founder mutations have been suggested to explain its current geographic distribution. OBJECTIVES: To trace back in history the main mutational events in Machado-Joseph disease, we aimed to assess ancestral haplotypes and population backgrounds, to date the mutations, and to trace the routes and time of introduction of the founder haplotypes in different populations. Design, Setting, and PARTICIPANTS: We studied 264 families with Machado-Joseph disease from 20 different populations. Six intragenic single-nucleotide polymorphisms were used to determine ancestral mutational events; 4 flanking short tandem repeats were used to construct extended haplotypes and measure accumulation of genetic diversity over time within each lineage. RESULTS: The worldwide-spread lineage, TTACAC, had its highest diversity in the Japanese population, where we identified the ancestral short tandem repeat-based haplotype. Accumulated variability suggested a postneolithic mutation, about 5774 +/- 1116 years old, with more recent introductions in North America, Germany, France, Portugal, and Brazil. As to the second mutational event, in the GTGGCA lineage, only 7 families (of 71 families) did not have Portuguese ancestry, although gene diversity was again smaller in Portuguese families (0.44) than in non-Portuguese families (0.93). CONCLUSIONS: The worldwide-spread mutation may have first occurred in Asia and later been diffused throughout Europe, with a founder effect accounting for its high prevalence in Portugal; the other Machado-Joseph disease lineage is more recent, about 1416 +/- 434 years old, and its dispersion may be explained mainly by recent Portuguese emigration.     

Linkage study of Machado-Joseph disease: genetic evidence for the locus different from SCA1]

Spinocerebellar ataxia 1 (SCA1) is the locus symbol of hereditary olivopontocerebellar atrophy, and it is mapped on the short arm of chromosome 6. D6S89 is the polymorphic DNA marker linked tightly to SCA1. In order to examine whether SCA1 and Machado-Joseph disease (MJD) loci are different from each other, we performed linkage study for D6S89 to MJD locus. A total of 20 pedigrees of MJD were analysed. Number of individuals consists of 211 members. Among them, 74 were affected. Consequently, 14 pedigrees showed negative lod score, and 6 showed weak positive lod scores at most of recombination fractions. As a whole, linkage between MJD locus and D6S89 was excluded at recombination fraction of 0.15. Our results further support the concept that MJD is not an allelic disorder but distinct genetic entity from SCA1.     

Association of the Tau haplotype with Parkinson's disease in the Greek population.

We compared the distribution of the Tau H1 haplotype and related subhaplotypes in a group of clinically diagnosed Parkinson's disease patients (n = 133) and in control individuals (n = 113) from northern Greece. We were able to detect a statistically significant overrepresentation of the H1H1 genotype in our patient group (OR for H1H1 vs. H1H2 and H2H2: 1.73; 95% CI: 1.03-2.90; P = 0.037). The H1 subhaplotype significantly associated with the disease in our population was different from the one previously reported for a Norwegian population, suggesting that the nature of the association of Tau with Parkinson's disease is influenced by ethnic variation.     

Inflammatory system gene polymorphism and the risk of stroke: a case-control study in an Indian population

Sequence variations in genes involved in inflammation system are known to contribute to the risk of cardiovascular diseases (CVD) including stroke. In this study, we performed a genetic association study on the single nucleotide polymorphisms (SNPs) present in the genes CD14 (-159 C/T), TNFalpha (-308 G/A), IL-1alpha (-889 C/T), IL-6 (-174 G/C), PSMA6 (-8 C/G), and PDE4D (SNP83 T/C, respectively) in order to discern their possible role in the susceptibility to stroke in a North Indian population. These SNPs were previously found to be associated with CVD through their contribution to inflammation. A case-control design was used to examine 176 stroke patients (112 ischemic and 64 hemorrhagic stroke patients) and 212 unrelated healthy control individuals. After adjustment for the confounding risk factors, the IL-1alpha -889 T allele carriers (TT+CT) were found to be strongly associated with both forms of stroke (OR=2.56; 95% CI=1.53-4.29; P=0.0004). The CC genotype of PDE4D was found to be associated only with ischemic stroke (OR=2.02; 95% CI=1.08-3.76; P=0.03). None of the variants tested for the CD14, TNFalpha, IL-6, and PSMA6 genes found to confer risk for stroke in the study population. In conclusion, the -889 C/T and SNP83 T/C SNPs of the IL-1alpha and PDE4D genes, respectively, appear to be genetic risk factors for stroke in our study population.     

Sexual assault history and headache: five general population studies.

Headache is a common and disabling symptom. Although it is known that sexual assault is associated with a wide range of physical symptoms, little research has addressed its association with headache. The present study evaluated this association in five independent samples of randomly selected household residents (pooled N = 7502). The weighted mean odds ratio (OR) linking sexual assault and headache, controlling age and education, was 1.70 (95% confidence interval [CI] = 1.40, 2.07). Odds ratios were homogeneous across studies, and were similar regardless of participants' gender or ethnicity. Persons sexually assaulted in childhood consistently had greater odds of headache than those first assaulted in adulthood (OR = 1.89, 95% CI = 1.19, 2.99). These results indicate that sexual assault, particularly in childhood, is associated with headache.     

Ethnic differences in the expression of neurodegenerative disease: Machado-Joseph disease in Africans and Caucasians.

We describe several families of African origin with SCA3/Machado-Joseph disease gene expansions. In these cases, the phenotype ranges from ataxia with parkinsonian signs to a syndrome clinically almost indistinguishable from idiopathic, L-dopa-responsive Parkinson's disease. In contrast, these parkinsonian phenotypes are rare in those of European descent. Haplotype analysis shows that these African families do not share a common founder, thus a cis-acting element in the promoter is unlikely to be responsible these unusual presentations. We suggest that trans-acting factors are responsible for the variable phenotype and discuss the implications of diseases showing racially different expressivities.     

Sleep apnea in Machado-Joseph disease: a clinical and polysomnographic evaluation

Objective/BackgroundMachado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is the most common type of autosomal dominant spinocerebellar ataxia (SCA). Sleep disorders have been described as frequent non-motor symptoms in MJD, and with marked impairment on quality of life. However, few studies have evaluated the frequency and characteristics of sleep apnea in MJD.Patients/MethodsThis study analyzed the prevalence of sleep apnea in 47 patients with MJD by using polysomnography. Clinical variables such as age, age at onset of symptoms, duration of symptoms (at time of evaluation), body index mass, ataxia scales severity and CAG repeat length were compared with polysomnographic findings.ResultsThirty four percent of MJD patients had OSAS, and 42.5% had excessive daytime somnolence. There were no differences considering ataxia severity, CAG repetition length or other clinical variable.ConclusionsPatients with MJD have high frequency of obstructive sleep apnea, and this sleep disorder is not correlated with ataxia severity, CAG repetition length or other clinical variable.     

Chronic pain in Machado-Joseph disease: a frequent and disabling symptom

BACKGROUND: Machado-Joseph disease (MJD) is one of the most common forms of neurodegenerative ataxia characterized by remarkable phenotypic heterogeneity. Although patients frequently report pain, systematic evaluation of this clinical feature is lacking. OBJECTIVES: To compare the frequency of chronic pain among patients with genetically confirmed MJD, an age- and sex-matched healthy control group, and a disease control group of patients with amyotrophic lateral sclerosis (ALS). METHODS: We included 70 patients with MJD, 20 patients with ALS, and 70 control subjects from 2 clinical centers. All individuals underwent assessment with a standardized pain questionnaire. In addition, we used a visual analog scale to quantify pain intensity. RESULTS: Thirty-three patients with MJD (47%), 3 patients with ALS (15%), and 6 controls (9%) reported chronic pain. Lower back pain preceded ataxia in 6 patients with MJD. Twenty-nine patients with MJD had daily pain, which was continuous in 23. The mean visual analog scale score was 6.1 in patients with MJD. Pain was musculoskeletal in 26 patients with MJD, dystonic in 2, neuropathic in 2, and mixed in 3. Typically, pain was lumbar (n = 17) or in the lower limbs (n = 15). We did not find significant differences regarding duration of disease, sex, or severity of ataxia among patients with MJD with and without chronic pain. Expanded (CAG)(n) tandem repeats were longer in patients with MJD who experienced chronic pain (67.3 vs 65.2; P = .04). CONCLUSIONS: In our series, pain was significantly more frequent in patients with MJD than in controls. Chronic pain was a frequent and often disabling complaint among patients with MJD. The lower back was the most frequently reported location of pain in patients with MJD.     

Evolution of the amygdala: new insights from studies in amphibians

The histology of amphibian brains gives an impression of relative simplicity when compared with that of reptiles or mammals. The amphibian telencephalon is small and contains comparatively few and large neurons, which in most parts constitute a dense periventricular cellular layer. However, the view emerging from the last decade is that the brains of all tetrapods, including amphibians, share a general bauplan resulting from common ancestry and the need to perform similar vital functions. To what extent this common organization also applies to higher brain functions is unknown due to a limited knowledge of the neurobiology of early vertebrates. The amygdala is widely recognized as a brain center critical for basic forms of emotional learning (e.g., fear conditioning) and its structure in amphibians could suggest how this capacity evolved. A functional systems approach is used here to synthesize the results of our anatomical investigations of the amphibian amygdala. It is proposed that the connectivity of the amphibian telencephalon portends a capacity for multi-modal association in a limbic system largely similar to that of amniote vertebrates. One remarkable exception is the presence of new sensory-associative regions of the amygdala in amniotes: the posterior dorsal ventricular ridge plus lateral nuclei in reptiles and the basolateral complex in mammals. These presumably homologous regions apparently are capable of modulating the phylogenetically older central amygdala and allow more complex forms of emotional learning.     

Molecular analysis of Huntington's disease and linked polymorphisms in the Indian population

OBJECTIVES: To understand the population variation and haplotypes of Huntington's disease (HD) in India we have analysed CAG repeats at the HD locus together with closely linked polymorphisms in both HD patients and normal controls. MATERIALS AND METHODS: The CAG repeat and linked polymorphisms were analysed in 30 Indian HD families together with 250 ethnically matched controls using fluorescent polymerase chain reaction (PCR) based size estimation. RESULTS: CAG repeats at the HD locus in the normal population showed a mean size of 17.99 +/- 2.66 repeats (range nine to 33 repeats). The HD mutation in our families did not show any significant association with either the (CCG)7 or (CCG)10 allele while haplotype analysis suggested the over-representation of the 7-2-I (CCG-D4s127-Delta 2642 loci) haplotype in a subset of families. CONCLUSION: The distribution of CAG repeats in the normal population suggests a higher prevalence of HD, closer to that seen in Western Europe. Haplotype analysis suggests the presence of a founder mutation in a subset of families and provides evidence for multiple and geographically distinct origins for the HD mutation in India.     

Machado-Joseph disease in Brazil: from the first descriptions to the emergence as the most common spinocerebellar ataxia

Machado-Joseph disease is an autosomal dominant inherited disorder of Azorean ancestry firstly described in 1972. Since then, several Brazilian researchers have studied clinical and genetic issues related to the disease. Nowadays, Machado-Joseph disease is considered the most common spinocerebellar ataxia worldwide. Machado-Joseph disease still has no specific therapy to arrest progression, but the unclear pathophysiological mechanism, features related to genetic characteristics, phenotype variability, apparently global involvement of the nervous system in the disease and the therapeutic challenges continue to attract investigators in the field of spinocerebellar ataxias. Brazilian researchers have distinguished themselves in the ongoing investigation seeking new knowledge about Machado-Joseph disease.     

Cognitive and olfactory deficits in Machado-Joseph disease: A dopamine transporter study

Cognitive and olfactory impairments have been demonstrated in patients with Machado–Joseph disease (MJD), and a possible relationship with dopaminergic dysfunction is implicated. However, there is still controversy regarding the pattern of striatal dopaminergic dysfunction in patients with MJD. In this study, we investigated whether these patients had different Dopamine Transporter (DAT) densities as compared to healthy subjects, and correlated these data with cognitive performance and sense of smell. Twenty-two MJD patients and 20 control subjects were enrolled. The neuropsychological assessment comprised the Spatial Span, Symbol Search, Picture Completion, Stroop Color Word Test, Trail Making Test and Phonemic Verbal Fluency test. The 16-item Sniffin' Sticks was used to evaluate odor identification. DAT imaging was performed using the SPECT radioligand [^99mTc]-TRODAT-1, alongside with Magnetic Resonance imaging. Patients with MJD showed significantly lower DAT density in the caudate (1.34 ± 0.27 versus 2.02 ± 0.50, p < 0.001), posterior putamen (0.81 ± 0.32 versus 1.32 ± 0.34, p < 0.001) and anterior putamen (1.10 ± 0.31 versus 1.85 ± 0.45, p < 0.001) compared with healthy controls. The putamen/caudate ratio was also significantly lower in patients compared with controls (0.73 ± 0.038 versus 0.85 ± 0.032, p = 0.027). Even though we had only two patients with parkinsonism, we detected striatal dopaminergic deficits in those patients. No significant correlations were detected between DAT density and cognitive performance or Sniffin' Sticks scores. The data suggests that striatal dopamine deficit is not involved in cognitive or sense of smell deficits. This finding raises the possibility of extra-striatal dopamine and other neurotransmitter system involvement or of cerebellum neurodegeneration exerting a direct influence on cognitive and sensorial information processing in MJD.