Spinocerebellar ataxia type 8 in Scotland: genetic and clinical features in seven unrelated cases and a review of published reports

OBJECTIVES: To establish whether the DNA expansion linked to spinocerebellar ataxia type 8 (SCA 8) is associated with ataxia in Scotland; to clarify the range of associated clinical phenotypes; and to compare the findings with previous reports. METHODS: DNA was screened from 1190 anonymised controls, 137 subjects who had tested negative for Huntington's disease, 176 with schizophrenia, and 173 with undiagnosed ataxia. Five unrelated ataxic patients with the SCA 8 expansion and a sixth identified subsequently had clinical and psychometric assessment; the clinical features were available in a seventh. A systematic search for other reports of SCA 8 was undertaken. RESULTS: Over 98% of SCA 8 CTA/CTG repeat lengths fell between 14 and 40. Repeat lengths over 91 were observed in three healthy controls (0.12%), two patients with suspected Huntington's disease (0.73%), and six ataxic subjects (1.74%; p<0.0005 v healthy controls). Repeat lengths over 100 occurred in five ataxic subjects but in only one control. All seven symptomatic subjects with the SCA 8 expansion had a cerebellar syndrome; four had upper motor neurone signs; and 5/6 assessed had cognitive complaints. There was personality change in two and mood disturbance in three. In published reports, SCA 8 repeat lengths over 91 occurred in approximately 0.5% of the healthy population but were over-represented among ataxic patients (3.4%; p<0.0001). The predominant clinical phenotype was cerebellar, with pyramidal signs in 50%, and neuropsychiatric features in some cases. CONCLUSIONS: SCA 8 expansion is a risk factor for a cerebellar syndrome, often associated with upper motor neurone and neuropsychiatric features. The expansion occurs unexpectedly often in the general population.     

MRI-based brain volumetry in chronic whiplash patients: no evidence for traumatic brain injury

Introduction –  Cognitive complaints, such as poor concentration and memory deficits, are frequent after whiplash injury and play an important role in disability. The origin of these complaints is discussed controversially. Some authors postulate brain lesions as a consequence of whiplash injuries. Potential diffuse axonal injury (DAI) with subsequent atrophy of the brain and ventricular expansion is of particular interest as focal brain lesions have not been documented so far in whiplash injury.
Objective –  To investigate whether traumatic brain injury can be identified using a magnetic resonance (MR)-based quantitative analysis of normalized ventricle–brain ratios (VBR) in chronic whiplash patients with subjective cognitive impairment that cannot be objectively confirmed by neuropsychological testing.
Materials and methods –  MR examination was performed in 21 patients with whiplash injury and symptom persistence for 9 months on average and in 18 matched healthy controls. Conventional MR imaging (MRI) was used to assess the volumes of grey and white matter and of ventricles. The normalized VBR was calculated.
Results –  The values of normalized VBR did not differ in whiplash patients when compared with that in healthy controls ( F  = 0.216, P  = 0.645).
Conclusions –  This study does not support loss of brain tissue following whiplash injury as measured by VBR. On this basis, traumatic brain injury with subsequent DAI does not seem to be the underlying mechanism for persistent concentration and memory deficits that are subjectively reported but not objectively verifiable as neuropsychological deficits.     

The 'hot cross bun' sign in the patients with spinocerebellar ataxia

Background and purpose:  The 'hot cross bun' sign (HCBS), typically seen in the patients with multiple system atrophy, refers to a cruciform hyperintensity in the pons on T2-weighted MRI. Little is known about its pathological basis and prevalence in other degenerative cerebellar diseases and healthy population. We investigate the frequency of HCBS in the patients with spinocerebellar ataxia (SCA) and healthy controls.
Methods:  The presence of HCBS on T2-weighted axial MRIs from 138 SCA patients (three SCA1, 35 SCA2, 76 SCA3, 18 SCA6, one SCA7, three SCA8, and two SCA17) and 102 healthy controls was evaluated retrospectively.
Results:  The overall prevalence of HCBS in the SCA patients is 8.7%, but the frequency varies in different subtypes: 25.7% in SCA2, 1.3% in SCA3, and none in SCA6 or healthy controls. Notably, one patient with SCA7 and one with SCA8 were also found to have HCBS.
Conclusions:  The differential list of HCBS should be expanded to include SCA7 and SCA8. The elucidation of frequency of HCBS in various SCA subtypes may help prioritize the genetic testing in late-onset dominant ataxia.     

Analysis of trinucleotide repeats in different SCA loci in spinocerebellar ataxia patients and in normal population of Taiwan

Objective – To identify various subtypes of spinocerebellar ataxias (SCAs) among autosomal dominant cerebellar ataxia (ADCA) patients referred to our research center, SCA1, SCA2, SCA3/MJD (Machado–Joseph disease), SCA6, SCA7, SCA8 and SCA12 loci were assessed for expansion of trinucleotide repeats.
Patients and methods – A total of 211 ADCA patients, including 202 patients with dominantly inherited ataxia from 81 Taiwanese families and nine patients with sporadic ataxia, were included in this study and subjected to polymerase chain reaction (PCR) analysis. The amplified products of all loci were analyzed on both 3% agarose gels and 6% denaturing urea-polyacrylamide gels. PCR-based Southern blots were also applied for the detection of SCA7 locus.
Results – The SCA1 mutation was detected in six affected individuals from one family (1.2%) with expanded alleles of 50–53 CAG repeats. Fourteen individuals from nine families (11%) had a CAG trinucleotide repeat expansion at the SCA2 locus, while affected SCA2 alleles have 34–49 CAG repeats. The SCA3/MJD CAG trinucleotide repeat expansion in 60 affected individuals from 26 families (32%) was expanded to 71–85 CAG repeats. As for the SCA7 locus, there were two affected individuals from one family (1.2%) possessed 41 and 100 CAG repeats, respectively. However, we did not detect expansion in the SCA6, SCA8 and SCA12 loci in any patient.
Conclusions – The SCA3/MJD CAG expansion was the most frequent mutation among the SCA patients. The relative prevalence of SCA3/MJD in Taiwan was higher than that of SCA2, SCA1 and SCA7.     

Spinocerebellar ataxias type 1, 2 and 3: a study of heart rate variability

Objective –  To detect cardiac autonomic dysfunction, using analysis of heart rate variability in genetically defined spinocerebellar ataxias (SCA).
Materials and methods –  Consecutive RR intervals were analyzed for time- and frequency- domain parameters in 22 genotypically proven SCA patients (SCA1 = 11, SCA2 = 6 and SCA3 = 5) and compared with that of age- and gender- matched controls.
Results –  Reduction in the standard deviation of RR interval (RR_SD) was seen in 72.7% of SCA patients. There was a reduction in both the parasympathetic and sympathetic parameters in SCA without any change in the ratio of low- to high- frequency power. In SCA1, there was a significant negative correlation between RR_SD and duration of illness but not with the CAG repeat lengths of the abnormal allele. Small sample size of SCA2 and SCA3 precluded similar comparison.
Conclusions –  Cardiac autonomic dysfunction, predominantly parasympathetic, was seen in SCA, and the severity correlated with the duration of illness in SCA1.     

Correlation among subcortical white matter lesions, intelligence and CTG repeat expansion in classic myotonic dystrophy type 1

Objectives –  To analyze the correlation among intelligence, brain magnetic resonance images (MRI) and genotype in classic myotonic dystrophy type 1 (DM1) patients.
Materials and methods –  Seventeen patients with classic DM1 were administered intelligence and neuropsychological tests and brain MRI focusing on a semi-quantitative rating scale of subcortical white matter lesions (WMLs). Statistical analysis was measured to evaluate the correlation among clinical manifestations, intelligence, brain MRI abnormalities, and CTG repeat expansion.
Results –  There were statistically significant correlations between intelligence test and insular WMLs for all DM1 patients and between intelligence quotient and temporal WMLs for those patients with less than 400 of the CTG repeat size. We also documented that temporal WMLs were related to the disease course, and frontal WMLs were correlated with aging in all DM1 patients. However, a poor correlation was found among CTG repeat size and clinical pictures, neuropsychological impairments, and brain MRI abnormalities in all DM1 patients.
Conclusion –  These results suggest that subcortical WMLs are correlated with focal dementia in classic DM1 patients. Temporal and insular WMLs may be responsible for the global intellectual dysfunction of adult DM1 patients.     

Cerebellar ataxia in the eastern and southern parts of Norway

Introduction –  The relative frequencies of different ataxias vary among different ethnic and geographic groups. The aim of this study was to examine patients with cerebellar ataxia and find the occurrence of autosomal dominant and recessive cerebellar ataxias in the population of the southern and eastern parts of Norway and estimate its prevalence.
Materials and methods –  Probands were systematically tested for spinocerebellar ataxia 1, 2, 3, 6 and Friedreich's ataxia. A total of 94 patients with ataxia were assessed.
Results –  We registered 60 patients from 39 unrelated families with hereditary ataxias. One family with SCA2 (two patients), one family with Friedreich's ataxia (two patients), two patients heterozygote for Friedreich's ataxia and one metabolic ataxia were identified.
Conclusions –  We have few Friedreich's ataxia and SCA 1,2,3 and 6 in our population. Prevalence in Oslo County was estimated at 2.2/100,000 for autosomal recessive and 3.0/100,000 for autosomal dominant ataxia, respectively.     

Cerebrospinal fluid tau and amyloid β42 protein in patients with myotonic dystrophy type 1

Background:  Myotonic dystrophy type 1 (DM1) is associated with brain morphology changes including neurofibrillary degeneration.
Methods:  We have examined cerebrospinal fluid (CSF) markers indicative of neuronal degeneration and amyloidogenesis; total tau (T-tau), phosphorylated tau (P-tau) and β amyloid_1–42 (Aβ42), in 32 patients with DM1.
Results and conclusions:  Associations between CSF markers and CTG repeat expansion size, brain MRI findings, and neuropsychological test results were analysed. As compared with matched controls Aβ42 was significantly decreased ( P  = 0.001), whilst levels of T-tau were increased ( P  < 0.001). No difference was found between measures considering P-tau levels. At present the clinical implications of these findings is unclear, because of an overlap between CSF values of DM1 patients and healthy controls, but also regarding modest associations between CSF markers and other measures. However notably, the Tau pathology, as seen in DM1, differs from Alzheimers disease, considering the lack of increased levels of P-tau.     

Neuropsychological Features of Patients with Spinocerebellar Ataxia (SCA) Types 1, 2, 3, and 6

A subtype-specific impairment of cognitive functions in spinocerebellar ataxia (SCA) patients is still debated. Thirty-two SCA patients (SCA1, 6; SC2, 3; SCA3, 15; SCA6, 8) and 14 matched healthy controls underwent neuropsychological evaluation testing attention, executive functions, episodic and semantic memory, and motor coordination. Severity of ataxia was assessed with the Scale for the Assessment and Rating of Ataxia (SARA), nonataxia symptoms with the Inventory of Non-Ataxia Symptoms. Depressive symptoms were evaluated with the Beck Depression Inventory. The SARA scores of our SCA patients (range 1–19.5) indicated an overall moderate ataxia, most pronounced in SCA6 and SCA1. Mean number of nonataxia symptoms (range 0–2.2) were most distinct in SCA1 and nearly absent in SCA6. SCA1 performed poorer than controls in 33% of all cognitive test parameters, followed by SCA2, SCA3, and SCA6 patients (17%). SCA 1–3 patients presented mainly attentional and executive dysfunctions while semantic and episodic memory functions were preserved. Attentional and executive functions were partly correlated with ataxia severity and fine motor coordination. All patients exhibited mildly depressed mood. Motor and dominant hand functions were more predictive for depressed mood than cognitive measures or overall ataxia. Besides motor impairments in all patients, SCA patients with extracerebellar pathology (SCA 1–3) were characterized by poor frontal attentional and executive dysfunction while mild cognitive impairments in predominantly cerebellar SCA6 patients appeared to reflect mainly cerebellar dysfunction. Regarding the everyday relevance of symptoms, (dominant) motor hand functioning emerged as a marker for the patient’s mood.     

Cognitive deficits in spinocerebellar ataxia type 1, 2, and 3

Cognitive impairment was studied in distinct types of spinocerebellar ataxia (SCA): eleven SCA1, 14 SCA2, and 11 SCA3 individuals and 8 age- and IQ- matched controls. All were submitted to a neuropsychological test battery that comprised tests for IQ, attention, executive function, verbal and visuospatial memory. Executive dysfunction was prominent in SCA1 as compared with controls and all other SCA types. Mild deficits of verbal memory were present in SCA1, SCA2 and SCA3. The neuropathological pattern in different SCA types suggests that these cognitive deficits are not likely to be contingent upon cerebellar degeneration but to result from disruption of a cerebrocerebellar circuitry presumably at the pontine level. Received: 26 November 2002, Received in revised form: 13 September 2002, Accepted: 24 September 2002 Correspondence to K. Bürk, MD     

Widespread neuronal damage and cognitive dysfunction in spinocerebellar ataxia type 3

Previous studies demonstrated cognitive impairments in spinocerebellar ataxia type 3 (SCA3/MJD); however, there is no consensus about the cognitive domains affected and the correlation with structural brain abnormalities. We investigated the neuropsychological profile and 3T-MRI findings, including high-resolution T1-images, diffusion tensor imaging and magnetic resonance spectroscopy of 32 patients with SCA3/MJD and 32 age-, gender- and educational level–matched healthy controls. We reviewed patients’ clinical history and CAG repeat length, and performed assessment and rating of ataxia (SARA)-Brazilian version and the neuropsychiatric inventory. Patients presented worse performance in episodic and working memory and Beck inventories (depression and anxiety). SCA3/MJD patients had a reduction of gray matter volume (GM) in the cerebellum, putamen, cingulum, precentral and parietal lobe. A positive correlation was identified between the cognitive findings and GM of temporal, frontal, parietal, culmen and insula. We observed positive correlation between the brainstem′s fractional anisotropy and digit span-forward. The following cerebellar metabolite groups (measured relative to creatine) were reduced in patients: N-acetyl-aspartate (NAA), NAA + N-acetyl-aspartate-glutamate and glutamate + glutamine (Glx). We found a positive correlation between Corsi’s block-tapping task forward with Glx; semantic verbal fluency with phosphorylcholine and glycerophosphorylcholine; digits span-forward with NAA. The cognitive impairments in SCA3/MJD are associated not only with cerebellar and brainstem abnormalities, but also with neuroimaging evidence of diffuse neuronal and axonal dysfunction, particularly in temporal, frontal, parietal and insular areas.     

Evaluation of cognition, structural, and functional MRI in juvenile myoclonic epilepsy

Purpose:  Previous studies using advanced imaging techniques have suggested subtle structural and functional changes in patients with juvenile myoclonic epilepsy (JME), mainly associated with the frontal lobes. In addition, it has been reported that these patients show neuropsychological deficits, often summarized as frontal lobe dysfunction. The aim of this study was a comprehensive analysis of neuropsychological parameters, and functional and structural magnetic resonance imaging (MRI) in an independent cohort of patients with JME.
Methods:  We studied 19 JME patients and 20 age-, sex-, and education-matched controls using a battery of standardized neuropsychological tests, optimized voxel-based morphometry (VBM), and two domain-specific working-memory paradigms combined with functional MRI (fMRI).
Results:  Our investigations did not reveal statistically significant differences between the groups of JME patients and normal controls in either the VBM or the fMRI study of working memory. The neuropsychological examination showed a slightly worse performance for the JME patients across most tests used, reaching statistical significance for semantic and verbal fluency.
Conclusions:  In our cohort of JME patients, we could not reproduce the findings of frontal gray matter changes from previous studies, and we could not detect an fMRI correlate of previously reported differences in working memory in JME. The neuropsychological deficits may be attributed partially to antiepileptic medication. We conclude that structural and functional frontal lobe deficits in JME patients have to be interpreted with care. One reason for a variation between different cohorts may be the genetic heterogeneity of the disease.     

Association of estrogen receptor-alpha gene polymorphisms with stroke risk in patients with metabolic syndrome

Objective –  The vascular protective effects of estrogens are mediated by their binding to the two known estrogen receptors. In this study, we examine the association of stroke with two common polymorphisms of the ESR1 gene in patients with metabolic syndrome.
Materials and methods –  DNA from 130 patients hospitalized for ischemic stroke and 240 healthy controls were genotyped for ESR1 Pvu II and Xba I polymorphisms.
Results –  Comparing female and male patients, it was found that CCGG diplotype is more frequent in male patients ( P  = 0.03). In addition, the AA genotype is associated with the onset of stroke at a younger age in the male patient group ( P  < 0.05).
Conclusions –  These findings suggest that Pvu II and Xba I polymorphisms may affect the age at onset of the first stroke and the probability of developing cerebrovascular disease.     

Hyperhomocysteinemia in patients with epilepsy: Does it play a role in the pathogenesis of brain atrophy? A preliminary report

Purpose:   Brain atrophy (BA) is observed in 20–50% of patients with epilepsy. Hyper-total-homocysteinemia (hyper-tHcy), which occurs in 10–40% of patients, is considered to be a risk factor for cardiovascular diseases and BA. The present study was aimed at investigating the possible association of hyper-tHcy with BA in a population of patients with epilepsy.
Methods:   Fifty-eight patients (33 M/25 F, 43.5 ± 13.1 years of age) chronically treated with antiepileptic drugs (AEDs) and 60 controls matched for age and sex were enrolled. All participants underwent determination of plasma tHcy, folate, vitamin B₁₂, and C677T methylene-tetrahydrofolate-reductase (MTHFR) polymorphism genotyping, and brain magnetic resonance imaging (MRI).
Results:   Patients exhibited significantly higher tHcy and lower folate levels than controls; hyper-tHcy was significantly associated with the variables group (patients vs. controls), MTHFR genotype, and their interaction terms. BA was observed in 30.1% of patients and was significantly associated with hyper-tHcy (β = 0.45, p = 0.003) and polytherapy (β = 0.31, p < 0.001).
Discussion:   Our investigation suggests that hyper-tHcy plays a role in the development of BA in patients with epilepsy. Although the real origin of this phenomenon is not yet fully elucidated, experimental data support the hypothesis of a link of the neuronal Hcy-mediated damage with oxidative stress and excitotoxicity.     

Lower dopamine transporter density in an asymptomatic patient with Kleine-Levin syndrome

Background –  Kleine–Levin syndrome (KLS) is a rare disorder whose pathophysiological mechanisms remain unknown.
Patients and methods –  To investigate dopamine abnormalities in KLS, a [^99mTc] – TRODAT-1 single photon emission computerized tomography (SPECT) was performed in a patient with KLS during the asymptomatic period and compared with three matched healthy controls.
Results –  The patient had 14% lower striatal dopamine transporter binding potential (DAT-BP) compared to the mean DAT-BP of three healthy controls.
Conclusion –  This study provides in vivo evidence for abnormalities in the DAT-BP, suggesting an involvement of the dopaminergic system in the pathophysiology of KLS.     

Autosomal dominant cerebellar ataxia: frequency analysis and clinical characterization of 45 families from Portugal

Background and purpose:  The relative frequency of the different autosomal dominant cerebellar ataxia (ADCA) varies widely amongst different geographic locations. Here we describe a series of 45 ADCA families from Portugal.
Methods:  Patients with progressive cerebellar dysfunction of autosomal dominant transmission underwent a clinical examination protocol and genetic testing for spinocerebellar ataxia (SCA)1 to Machado-Joseph disease (MJD)/SCA3, SCA6, SCA7, SCA10, SCA12, SCA17 and dentatorubral-pallidoluysian atrophy (DRPLA). We registered the clinical characteristics and frequency of each type of ataxia.
Results:  MJD/SCA3 was the most frequent ADCA (26 families, 57.8% of all families), followed by DRPLA (5 families, 11.2%), SCA7 (2 families, 4.4%), SCA2 and SCA1 (1 family each, 2.2% each); 10 families (22.2%) had no molecular diagnosis. SCA1 and SCA7 patients had African ancestry. DRPLA patients had Portuguese ancestry and were characterized by prominent anticipation and a variable combination of epilepsy, extra-pyramidal symptoms and dementia. Ophtalmoparesis, slow saccades and retinopathy were most distinctive of SCA3, SCA2 and SCA7 cases, respectively.
Conclusions:  MJD/SCA3 was the most common ADCA in this group of families. The high frequency of DRPLA and presence of SCA1 and SCA7 cases was unexpected. The presence of these rarer ADCA types probably reflects migration phenomena, posing a challenge for differential diagnosis.     

Structural Changes Associated with Progression of Motor Deficits in Spinocerebellar Ataxia 17

Spinocerebellar ataxia (SCA17) is a rare genetic disorder characterized by a variety of neuropsychiatric symptoms. Recently, using magnetic resonance imaging (MRI) voxel-based morphometry (VBM), several specific functional–structural correlations comprising differential degeneration related to motor and psychiatric symptoms were reported in patients with SCA17. To investigate gray matter volume (GMV) changes over time and its association to clinical neuropsychiatric symptomatology, nine SCA17 mutation carriers and nine matched healthy individuals underwent a detailed neuropsychiatric clinical examination and a high-resolution T1-weighted volume MRI scan, both at baseline and follow-up after 18 months. Follow-up images revealed a progressive GMV reduction in specific degeneration patterns. In contrast to healthy controls, SCA17 patients showed a greater atrophy not only in cerebellar regions but also in cortical structures such as the limbic system (parahippocampus, cingulate) and parietal precuneus. Clinically, progression of motor symptoms was more pronounced than that of psychiatric symptoms. Correlation with the clinical motor scores revealed a progressive reduction of GMV in cerebellar and cerebral motor networks, whereas correlation with psychiatric scores displayed a more widespread GMV impairment in frontal, limbic, parietal, and also cerebellar structures. Interestingly, changes in global functioning were correlated with bilateral atrophy within the para-/hippocampus. While there was a good temporal association between worsening of motor symptoms and progression in cerebral and cortical neurodegeneration, the progression in psychiatric related neurodegeneration seemed to be more widespread and complex, showing progressive atrophy that preceded the further development of clinical psychiatric symptoms.     

Clinical features and natural history of spinocerebellar ataxia type 1

SCA1 is a dominant spinocerebellar ataxia (SCA) and a multi-systemic syndrome caused by abnormal expansion of unstable CAG repeat in a novel gene located on chromosome 6p22–p23. We clinically studied 35 Japanese SCA1 patients who were assumed to have come from a common origin. The age at onset ranged from 15–63 years, and significantly correlated with CAG repeat units of mutant alleles. Ataxia was the initial symptom, and the majority of patients had a similar history of signs and symptoms. Nystagmus was at first minimal, later attenuated, and a slow saccade followed. Limb tendon reflexes were mostly hyperactive and depressed with the development of diffuse amyotrophy. The cardinal feature was ataxia-hyperreflexia-late slow saccade syndrome with terminal amyotrophy. Although the phenotype of SCA1 overlaps with those of other dominant SCAs, some facets of the neurological events differ from either SCA2 with ataxia-hyporeflexia-slow saccade syndrome, or early-onset Machado-Joseph disease with dystonia-bradykinesia-spasticity syndrome.     

Elderly People and Epilepsy: Cognitive Function

Summary:  Purpose: To evaluate cognitive function in a group of elderly patients with focal epilepsy versus healthy controls.
Methods: A neuropsychological battery assessing major cognitive domains was administered to 40 patients with focal epilepsy aged ≥60 years, and to 40 controls matched for sex, age, and education.
Results: Epilepsy patients performed significantly worse in most of the administered tests than controls (p < 0.05). Poor cognitive performances correlated with use of polytherapy.
Conclusions: Given the high prevalence of epilepsy in the elderly, our results could have important implications for clinical and research purposes.     

Neuropsychological and functional MRI studies provide converging evidence of anterior language dysfunction in BECTS

Purpose:   Benign childhood epilepsy with centrotemporal spikes (BECTS) is the most common epilepsy syndrome of childhood and can be associated with language difficulties. The exact profile of these difficulties and their neurofunctional underpinnings, however, are not yet clear.
Methods:   To further understand the impact of the BECTS syndrome on language, we assessed language performance using standard neuropsychological measures, and patterns of language lateralization using functional magnetic resonance imaging (fMRI) in children with typical BECTS (n = 20) and healthy controls (n = 20).
Results:   The fMRI analyses revealed that language-related activation was less lateralized to the left hemisphere in anterior brain regions in the patients relative to the control group. This finding was consistent with decreased performance in the BECTS group compared to the control group on the neuropsychological measure most dependent on the integrity of anterior aspects of the language axis, namely, sentence production.
Discussion:   The converging lines of evidence from the neuropsychological and activation methodologies support the view that BECTS is associated with language difficulties that are regional, and anterior, in nature.