Cerebrotendinous xanthomatosis: a rare cause of spinocerebellar syndrome

A 34-year-old patient demonstrating pyramidal and cerebellar signs, accompanied by epilepsy, peripheral neuropathy, mental retardation and bilateral cataract was diagnosed with cerebrotendinous xanthomatosis based on the clinical picture, magnetic resonance imaging of the brain and serum sterol analysis. Tendon xanthomas were not observed in this case. After establishing the diagnosis, treatment with chenodeoxycholic acid and statin was introduced. During the next two years of the follow-up, serum cholestanol and 7α-hydroxycholesterol levels decreased in response to the therapy, but this was not reflected in the patient's neurological condition, which was slowly progressing. Treatment effectiveness in cerebrotendinous xanthomatosis is variable, notably better in patients who had started therapy before the injury to the nervous system took place. The present case report points to cerebrotendinous xanthomatosis as a rare cause of spinocerebellar syndrome, which might be treatable if diagnosed in early life.     

Refinement of the spinocerebellar ataxia type 4 locus in a large German family and exclusion of CAG repeat expansions in this region

Spinocerebellar ataxia type 4 (SCA4) is an autosomal dominant disorder mapped to chromosome 16q22.1 in a large Utah kindred. The clinical phenotype is characterized by cerebellar ataxia with sensory neuropathy. We describe a five-generation family from northern Germany with similar clinical findings linked to the same locus. Haplotype analyses refined the gene locus to a 3.69 cM interval between D16S3019 and D16S512. Analysis of nine CAG/CTG tracts in this region revealed no evidence for a repeat expansion. Received: 28 October 2002, Received in revised form: 16 December 2002, Accepted: 19 December 2002 Correspondence to: Dr. Yorck Hellenbroich     

Rapid detection of large expansions in progressive myoclonus epilepsy type 1, myotonic dystrophy type 2 and spinocerebellar ataxia type 8

Background and purposeHuman genetic disorders associated with multiple unstable repeats resulting in long DNA expansions are difficult to identify by conventional polymerase chain reaction (PCR) in routine molecular testing, and therefore require time-consuming hybridisation. To improve and expedite the diagnostic methods for progressive myoclonus epilepsy (EPM1), myotonic dystrophy 2 (DM2) and spinocerebellar ataxia 8 (SCA8) caused by dynamic mutations, we adapted a repeat primed PCR (RP-PCR) assay which was previously developed for testing of other triplet repeat disorders.Material and methodsThe new algorithm for molecular analysis was to run a standard PCR to yield alleles in an amplifiable range and then run a RP-PCR to detect larger expansions. Electrophoresis and visualisation of PCR products on an automatic sequencer were applied to determine normal and pathogenic alleles comprising (C₄GC₄GCG)_n in EPM1 in 44 subjects, (CCTG)_n in DM2 in 76 individuals and (CTG)_n in SCA8 in 378 patients. Results: The protocol combining conventional PCR and RP-PCR proved to be a rapid and reliable test to diagnose the above named disorders. Among 44 individuals tested for EPM1, two expanded alleles were identified in 7 patients. Out of 76 apparently homozygous subjects, RP-PCR allowed us to detect 56 expansions specific to DM2, and out of 378 ataxia patients, a large allele of the ATXN8OS gene (SCA8) was found in 25 subjects.ConclusionsHere, for the first time, we report detection of large expansions in EPM1 and SCA8 patients. This RP-PCR assay is high throughput, reproducible and sensitive enough to be successfully used for diagnostic purposes.     

The clinical diagnosis of autosomal dominant spinocerebellar ataxias

The spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal dominantly inherited progressive ataxia diseases. Up to now, almost 30 different gene loci have been found. In 14 of them, the underlying mutations have been identified. The more common SCAs, SCA1, 2, 3 and 6 are due to translated CAG repeat expansions that code for an elongated polyglutamine tract within the respective proteins. These diseases belong to a larger group of polyglutamine disorders that also includes Huntington’s disease. Epidemiological studies conducted in different European regions found prevalence rates of SCAs ranging from 0.9 to 3.0:100,000. In all SCAs, ataxia is the prominent symptom. However, the majority have a complex phenotype in which ataxia is accompanied by varying non-ataxia symptoms. In all ataxia patients with proven or suspected autosomal dominant mode of inheritance, the available molecular genetic tests for SCA mutations should be performed. Depending on the geographical origin of the family, these tests will lead to positive diagnostic results in at least half of the families.     

Prevalence of spinocerebellar ataxia type 2 mutation among Italian Parkinsonian patients.

We evaluated the prevalence of the SCA2 mutation among 224 Italian patients affected by typical Parkinsonism, including 145 sporadic and 79 familial forms. Pink1, Parkin, and LRRK2 gene mutations had been excluded previously. Molecular testing for the CAG expansion at the SCA 2 locus was performed on leukocyte DNA. Cloning and sequencing of the expanded allele was performed in patients positive for the SCA2 expansion. A 38 CAG expansion was detected in 1 of 79 families studied. The proband, a male age 67, and his sister, age 69, were both affected by a benign form of L-dopa-responsive Parkinsonism not associated with cerebellar signs. The inheritance was autosomal dominant. The CAG expansion was stable through meiotic transmission: sequence analysis showed that the CAG stretch was interrupted by 3 CAA. Our study shows that CAG expansion at the SCA 2 locus may represent a genetic cause of familial L-dopa-responsive Parkinsonism among Italian patients. The stability of the pathological CAG expansion detected in this family was related to the presence of CAA interruptions. These findings, together with literature data, suggest that the molecular intrinsic structure of the expanded allele may modulate the phenotypic expression of the SCA2 mutation.     

Absence of spinocerebellar ataxia type 3/Machado–Joseph disease within ataxic patients in the Czech population

Although spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease is the most common type of SCA worldwide, we did not identify any cases of the disease amongst SCA patients in the Czech population. It has been proposed that the prevalence of large normal alleles correlates with the frequency of various types of SCA. We have therefore attempted to resolve the absence of SCA3 in our population by investigating, within 204 normal chromosomes, the frequency and nature of CAG repeats as well as two intragenic polymorphisms. We found that large normal alleles with more than 33 CAG repeats were observed at a frequency of only 0.49%. Whereas most of the expanded alleles worldwide have the CA haplotype, this was the least common (5.4%) variant observed in our study, although it was associated with a larger mean CAG repeat length (26.9). We postulate that the absence of SCA3 in the Czech population might be explained by the lack of large normal alleles and consequently a relatively small reservoir for aberrant CAG expansions at the SCA3 locus.     

The occurrence of dominant spinocerebellar ataxias among 251 Finnish ataxia patients and the role of predisposing large normal alleles in a genetically isolated population

OBJECTIVES: Frequency and distribution of dominant ataxias caused by dynamic mutations may vary in different populations, which has been explained on the basis of relative frequency of predisposing normal alleles. The aim of the study was to evaluate the occurrence of spinocerebellar ataxias (SCAs) and dentatorubral-pallidoluysian atrophy (DRPLA) in Finland, and to investigate the role of predisposing normal alleles in a genetically homogenous population. MATERIAL AND METHODS: Mutation analyses for SCA1, 2, 3, 6, 7, 8, 10, 12, 17, and DRPLA and frataxin genes were performed for 251 unrelated Finnish patients who presented with progressive ataxia disorder. RESULTS: Expansions of SCA1, SCA2, SCA6, SCA7, SCA8, and SCA17 genes were detected in 2, 1, 1, 7, 22, and 1 patients, respectively. Altogether, 39 and 7% of dominant and sporadic SCA patients, respectively, harboured expansions at some of the investigated loci. Normal variation, collected from 477 to 502 chromosomes at each disease loci, revealed that Finns were different from the Japanese but largely similar to other Caucasians. CONCLUSIONS: Lack of SCA3 and excess of SCA8 are characteristic to the Finnish population. Homozygosity for the SCA8 expansion increases penetrance. Frequencies of large normal alleles at the SCA loci predict poorly prevalence of the respective diseases in Finland. Prioritization in DNA testing, based on ethnic origin and geographical location, is recommendable in Finland, and analogous approach may be applied to other countries as well.     

Disturbance of rapid eye movement sleep in spinocerebellar ataxia type 2.

Five genetically confirmed spinocerebellar ataxia type 2 (SCA2) patients were admitted to our sleep laboratory for two all-night video-polysomnographies. A standard montage was used, including electroencephalography, vertical and horizontal electrooculography, electromyography of mental, submental, and tibialis anterior muscles, and respiratory monitoring. Four of five SCA2 patients had insufficient muscle atonia during rapid eye movement (REM) sleep. All patients exhibited myoclonic jerks during REM sleep, while elaborated behavior was not observed in the video. Abnormal motor control during sleep with periodic leg movements and REM sleep without atonia occurs frequently in SCA2. This finding may reflect a dysfunction of dopaminergic and/or brainstem and cerebellar outflow pathways.     

Evidence for a relatively high proportion of DM2 mutations in a large group of Polish patients

Introduction

Myotonic dystrophies (DMs) type 1 (DM1) and type 2 (DM2) are autosomal dominant, multisystem disorders, considered the most common dystrophies in adults. DM1 and DM2 are caused by dynamic mutations in the DMPK and CNBP genes, respectively.

Urine levels of the polyglutamine ataxin-3 protein are elevated in patients with spinocerebellar ataxia type 3

IntroductionAccumulation of polyglutamine (polyQ) ataxin-3 (ATXN3) contributes to the pathobiology of spinocerebellar ataxia type 3 (SCA3). Recently, we showed that polyQ ATXN3 is elevated in the plasma and cerebrospinal fluid (CSF) of SCA3 patients, and has the potential to serve as a biological marker for this disease [1]. Based on these findings, we investigated whether polyQ ATXN3 can also be detected in urine samples from SCA3 patients.MethodsWe analyzed urine samples from 30 SCA3 subjects (including one pre-symptomatic subject), 35 subjects with other forms of ataxia, and 37 healthy controls. To quantify polyQ ATXN3 protein levels, we used our previously developed immunoassay.ResultsPolyQ ATXN3 can be detected in the urine of SCA3 patients, but not in urine samples from healthy controls or other forms of ataxia. There was a significant statistical association between polyQ ATXN3 levels in urine samples and those in plasma. Further, the levels of polyQ ATXN3 urine associated with an earlier age of SCA3 disease onset.ConclusionAs clinical trials for SCA3 advance, urine polyQ ATXN3 protein has potential to be a useful, non-invasive and inexpensive biomarker for SCA3.     

Reduced brain‐derived neurotrophic factor (BDNF) mRNA expression and presence of BDNF‐immunoreactive granules in the spinocerebellar ataxia type 6 (SCA6) cerebellum

Spinocerebellar ataxia type 6 (SCA6) is an autosomal‐dominant neurodegenerative disorder caused by a small expansion of tri‐nucleotide (CAG) repeat encoding polyglutamine (polyQ) in the gene for α_1A voltage‐dependent calcium channel (Ca_v2.1). Thus, this disease is one of the nine neurodegenerative disorders called polyQ diseases. The Purkinje cell predominant neuronal loss is the characteristic neuropathology of SCA6, and a 75‐kDa carboxy‐terminal fragment (CTF) of Ca_v2.1 containing polyQ, which remains soluble in normal brains, becomes insoluble in the cytoplasm of SCA6 Purkinje cells. Because the suppression of the brain‐derived neurotrophic factor (BDNF) expression is a potentially momentous phenomenon in many other polyQ diseases, we implemented BDNF expression analysis in SCA6 human cerebellum using quantitative RT‐PCR for the BDNF mRNA, and by immunohistochemistry for the BDNF protein. We observed significantly reduced BDNF mRNA levels in SCA6 cerebellum (n = 3) compared to controls (n = 6) (Mann–Whitney U‐test, P = 0.0201). On immunohistochemistry, BDNF protein was only weakly stained in control cerebellum. On the other hand, we found numerous BDNF‐immunoreactive granules in dendrites of SCA6 Purkinje cells. We did not observe similar BDNF‐immunoreactive granules in other polyQ diseases, such as Huntington's disease or SCA2. As we often observed that the 1C2‐positive Ca_v2.1 aggregates existed more proximally than the BDNF‐positive granules in the dendrites, we speculated that the BDNF protein trafficking in dendrites may be disturbed by Ca_v2.1 aggregates in SCA6 Purkinje cells. We conclude that the SCA6 pathogenic mechanism associates with the BDNF mRNA expression reduction and abnormal localization of BDNF protein.     

Presenile onset of spinocerebellar ataxia type 1 presenting with conspicuous psychiatric symptoms and widespread anti‐expanded polyglutamine antibody‐ and fused in sarcoma antibody‐immunopositive pathology

A 50‐year‐old Japanese man showed slowly progressive gait disturbance and dysarthria. Neurological examination 5 years after onset revealed slow eye movement with nystagmus as well as limb and truncal ataxia. Magnetic resonance imaging showed atrophy of the cerebellum and brainstem. Because genetic examination revealed CAG repeat expansion of the ataxin‐1 gene, the patient was diagnosed with spinocerebellar ataxia type 1. Ten years after onset, he showed psychiatric symptoms with cognitive impairment, and antipsychotic drugs were administered. As psychiatric symptoms gradually worsened, particularly with regard to resisting nursing care and shouting, the doses of the drugs were increased. Although the clinicopathologic findings were generally identical to previously reported spinocerebellar ataxia type 1 cases with the exception of the conspicuous psychiatric symptoms, there are two notable immunohistochemical findings. Firstly, numerous anti‐expanded polyglutamine antibody‐immunopositive neuronal inclusions were extensively observed, including in the cerebral cortex and limbic system, but not in the Purkinje cells. Secondly, anti‐fused in sarcoma antibody‐immunopositive intranuclear inclusions were extensively observed. We posit that the anti‐expanded polyglutamine antibody‐immunopositive neuronal inclusions and possibly the anti‐fused in sarcoma antibody‐immunopositive inclusions, particularly those in the neocortex and limbic system, may correspond to the psychiatric symptoms and cognitive impairment that were observed in the patient.     

Cross-correlation analysis of the response of units in the dorsal spinocerebellar tract (DSCT) to muscle stretch and contraction

Activity of DSCT units was cross-correlated with stimuli evoking gastrocnemius-soleus muscle stretch or contraction in order to investigate the muscle receptor input to DSCT. The most potent stimulus was generally muscle contraction, and the most common response one of inhibition. The similarity in response of many units to stretch, contraction and nerve simulation suggests that Golgi tendon organs are a prominent source of input to DSCT, and that much of this input is inhibitory.     

Assessment of explicit and implicit linguistic impairments in patients with aphasia after resection of tumour of the left cerebral hemisphere. Preliminary results

Background and purposeClassical definitions of aphasia describe deficits of different language levels (syntactic, semantic, phonologic) hindering the ability to communicate. Recent studies indicate, however, that impairment of particular aspects of linguistic competencies in aphasia differs in severity. Contemporary approach to the aphasic symptoms presents them as disturbed access of linguistic representations to the awareness system. Accordingly, such an approach requires different types of tasks: direct, involving explicit language processes, and indirect, based on implicit language representations. The aim of our study was to examine explicit and implicit language processes in patients with aphasia after resection of the tumour of left cerebral hemisphere along with characterization of relationships between explicit and implicit language processes.Material and methodsOur cohort included 28 right-handed patients who were divided into four equal groups: two clinical (brain tumours) and two control (lumbar disc disease). Four tasks that assess and compare language processes: lexical decisions (at explicit and implicit levels), sorting of picture captions and word monitoring were implemented.ResultsIn direct tasks, patients with aphasia provided less correct lexical decisions at word level, but did not show deficits in sentence comprehension. In both groups, no priming effect was observed in tasks requiring implicit lexical decisions. The longest time was found in non-primed words, the shortest in pseudowords. The differences between groups regarding word monitoring were also observed. Patients with aphasia obtained longer reaction times in all types of sentences (of different grade of language correctness), with respect to low- and high- frequency words.ConclusionsPatients with aphasia after brain tumour resection show more pronounced impairments of explicit than implicit linguistic behavior; the same effect was found in studies on forgetting in amnestic syndrome.     

The analysis of selected neurotransmitter concentrations in serum of patients with Tourette syndrome

Background and purposeMetabolic disturbances of excitatory and inhibitory neurotransmitters are implicated in pathogenesis of Tourette syndrome (TS). The aim of the study was to measure serum concentrations of glutamic acid, γ-aminobutyric acid (GABA) and glycine in TS patients and evaluate any correlation between neurotransmitter levels and age at onset, actual age, gender, tic severity, duration of the disease and concomitant psychiatric disorders.Material and methodsSixty-seven TS patients, aged 16–59, and 57 healthy controls, aged 19–37, were enrolled in the study. Information regarding medical history and physical investigation was collected using a short questionnaire. Sixty-seven percent of patients were medication-free at the time of examination and the rest had withheld treatment for 24 hours before. Blood samples were taken after a 12-hour fasting period. HPLC technique was used.ResultsThe TS group had higher glutamic acid and lower GABA levels. Glycine concentrations were comparable. No differences regarding neurotransmitter concentrations between treated and non-treated patients were found. Patients with concomitant obsessive-compulsive disorder and severe tics had higher glutamate levels. Glutamate concentrations correlated positively with the number of comorbid psychiatric disorders and GABA concentrations correlated negatively with the number of behavioural problems in patients with comorbidities. There was no correlation between analysed neurochemicals and age, gender, age at onset or disease duration.ConclusionsImbalance between excitatory and inhibitory systems in the brains of TS patients may be reflected by glutamate and GABA serum level changes. Glutamate and GABA may be biomarkers of the disease and high concentration of glutamate may indicate more severe course of TS.     

Evaluation of single bolus,dual-echo dynamic susceptibility contrast MRI protocols in brain tumor patients

Relative cerebral blood volume (rCBV) obtained from dynamic susceptibility contrast (DSC) MRI is adversely impacted by contrast agent leakage in brain tumors. Using simulations, we previously demonstrated that multi-echo DSC-MRI protocols provide improvements in contrast agent dosing, pulse sequence flexibility, and rCBV accuracy. The purpose of this study is to assess the in-vivo performance of dual-echo acquisitions in patients with brain tumors (n = 59). To verify pulse sequence flexibility, four single-dose dual-echo acquisitions were tested with variations in contrast agent dose, flip angle, and repetition time, and the resulting dual-echo rCBV was compared to standard single-echo rCBV obtained with preload (double-dose). Dual-echo rCBV was comparable to standard double-dose single-echo protocols (mean (standard deviation) tumor rCBV 2.17 (1.28) vs. 2.06 (1.20), respectively). High rCBV similarity was observed (CCC = 0.96), which was maintained across both flip angle (CCC = 0.98) and repetition time (CCC = 0.96) permutations, demonstrating that dual-echo acquisitions provide flexibility in acquisition parameters. Furthermore, a single dual-echo acquisition was shown to enable quantification of both perfusion and permeability metrics. In conclusion, single-dose dual-echo acquisitions provide similar rCBV to standard double-dose single-echo acquisitions, suggesting contrast agent dose can be reduced while providing significant pulse sequence flexibility and complementary tumor perfusion and permeability metrics.     

A comparison of the results of carpal tunnel release in patients in different age groups

Background and purposeThe age of the patient at the onset of the disease may influence its course and outcome of the treatment. The objective of this study was to compare outcomes of carpal tunnel release in patients in different age ranges.Material and methodsThe records from the register of patients with carpal tunnel syndrome who were operated on in the authors’ department over a period of two years (between 2009 and 2011) were analyzed. A total of 386 patients with carpal tunnel syndrome, 322 female (83%) and 64 male (17%) with a mean age of 57 (range: 30–81) years were divided into three sub-groups according to their age: 40 years or less (n = = 28), 41–65 years (n = 248) and over 65 years (n = 73). All patients received mini-open carpal tunnel release. The results were assessed at 6 months after the operation by the Levine questionnaire and measurements of grip and pinch strengths as well as sensation of a light touch by the filament test.ResultsAt the six-month follow-up, all patients showed significant resolution of symptoms as assessed by the Levine symptom score (from 3.3 to 1.4) and significant improvement of the dexterity of the hand, as assessed by the Levine function score (from 3.0–3.2 to 1.6–1.8). All patients showed significant improvement of sensation of a light touch and increase of grip and pinch strengths. However, patients older than 60 years showed less improvement of the total grip strength of the hand.ConclusionPatients with carpal tunnel syndrome at any age may expect a similar benefit from surgery.     

Expansion of the phenotypic spectrum of SCA14 caused by the Gly128Asp mutation in PRKCG

Two cases of spinocerebellar ataxia type 14 (SCA14) with a G128D mutation in the protein kinase C gamma gene (PRKCG) without a definite family history have been reported previously. Here, we describe the first familial cases of SCA14 with a G128D mutation in PRKCG. Among three family members, the chief complaints varied and included ataxic gait, cervical dystonia, and positional vertigo. Moreover, retinal degeneration and facial muscle weakness were observed, although these are not expected to be present in SCA14. Cerebral blood flow evaluation using single photon emission computed tomography (SPECT) also differed among family members. It is possible that patients with the G128D mutation suffering from SCA14 may sometimes be classified as unaffected due to the varying clinical signs among family members.     

下肢骨折致膝关节功能障碍患者骨密度与早期康复训练的关系

背景：将骨密度检测同康复治疗相关联将有益于患者及康复治疗师及时了解康复进程,为康复治疗师制定或修改康复方案提供更好的依据。但目前国内有关康复治疗对人体骨密度影响的报道相对较少。目的：观察综合康复训练对下肢骨折致膝关节功能障碍患者骨密度的影响,并比较其性别差异。方法：选择天津医院康复科下肢骨折致膝关节功能障碍行内固定或外固定患者80例,随机分为康复组与对照组。康复组在术后4周开始进行早期康复治疗,包括主动、被动运动训练及不同物理治疗,持续20周;对照组在术后24周内未进行系统的康复训练。术后4,24周双能X射线检测股骨颈、L2~4、Ward区骨密度,并测量患者膝关节活动度。 结果与结论：无论是否进行早期运动康复训练及锻炼,下肢制动患者股骨颈、L2~4以及Ward区骨密度均下降,但康复组与对照组骨密度下降程度不同,康复组各部位骨密度的减少量均低于对照组(P < 0.01),关节活动增加程度明显大于对照组(P < 0.01),说明运动康复训练可以有效地减少下肢骨折患者康复期间骨矿物质的丢失,减少局部骨密度下降量,有效预防和改善失用性骨质疏松的情况,并且早期运动康复对下肢骨折所致膝关节功能障碍患者骨密度的影响并无明显的性别差异。