Presence of spinocerebellar ataxia type 2 gene mutation in a patient with apparently sporadic Parkinson's disease: clinical implications.

Among 242 patients with apparently sporadic Parkinson's disease, a 70-year-old man with a CAG repeat number of 37 in the SCA2 gene was identified. He has remained responsive to levodopa 14 years after onset and has had no overt signs suggesting cerebellar dysfunction. Although it is not possible to confirm if this patient has a de novo mutation of the SCA2 gene, this genetic defect seems to be contributing to his parkinsonian features and further supports the concept that apparently sporadic, late-onset, levodopa-responsive Parkinson's disease may have multiple causes.     

Profile of families with parkinsonism-predominant spinocerebellar ataxia type 2 (SCA2).

Spinocerebellar ataxia type 2 (SCA2) has been recognized recently as an uncommon cause of parkinsonism, an alternate presentation to the typical cerebellar disorder. This research review summarizes the existing literature on parkinsonism-predominant presentation SCA2 and presents new clinical cases of patients with this condition. Various phenotypes are noted in this subtype of SCA2, including parkinsonism indistinguishable from idiopathic Parkinson's disease (PD), parkinsonism plus ataxia, motor neuron disease, and postural tremor. In several kindreds with multiple affected family members, the SCA2 expansion segregated with disease; in addition, several single cases of parkinsonism with and without a family history are also described. The number of repeats in symptomatic patients ranged from 33 to 43. Interruption of the CAG repeat with CAA, CGG, or CCG was found in some individuals, possibly stabilizing the repeat structure and accounting for the relative stability of the repeat size across generations in some families; allele length is not necessarily indicative of trinucleotide repeat architecture. Positron emission tomography scanning in one family showed reduced fluorodopa uptake and normal to increased raclopride binding with a rostrocaudal gradient similar to that found in idiopathic PD. This review emphasizes the importance of testing for SCA2 in patients with parkinsonism and a family history of neurodegenerative disorders. Testing for SCA2 is also important in studies of inherited parkinsonism.     

Dystonia in spinocerebellar ataxia type 6.

Spinocerebellar ataxias are heterogeneous disorders with overlapping clinical features. Spinocerebellar ataxia-6 is a dominantly inherited condition characterized by relatively pure ataxia with a paucity of other manifestations including extrapyramidal findings. We report on two patients with genetically proven SCA-6 who had dystonia. One patient presented initially with dystonia, which remained the most disabling problem. Dystonia may occur in SCA-6 and can be disabling.     

Identification of the spinocerebellar ataxia type 7 mutation in Taiwan: application of PCR-based Southern blot

Spinocerebellar ataxia (SCA) type 7 is an autosomal dominant disorder characterized by neural loss, mainly in the cerebellum and regions of the brainstem and particularly the inferior olivary complex. This neurodegeneration disease is associated with expansion of unstable CAG repeats within the 5'-translated region of the SCA7 gene, located on chromosome 3p. We conducted a local survey of the normal population and candidate patients for the analysis of the CAG repeats in the SCA7 gene. The distributions of the CAG repeat units of SCA7 gene in the normal population in Taiwan were established in this study by using the radioactive genomic polymerase chain reaction (PCR). The normal range of CAG repeats is from 6 to 17 repeats, with the more common being around 8-13 repeats. The range is narrower than that reported for other ethnic groups (7-35 CAGs). Meanwhile, by the use of a combination of PCR and Southern blot analysis, one SCA7 family was identified and is reported here. A marked instability of the CAG repeat number during transmission from father to son (41 vs. 100) was observed in the SCA7 family. Clinical anticipation is significant in this family including an infantile case, who was found to have nystagmus from the age of 1 month. To date, the SCA7 mutation has been detected in one of 73 families with autosomal dominant cerebellar ataxia phenotypes, which is about 1.4% of the ataxia families referred to us, compared to 1.4% SCA1, 9.6% SCA2, and 27.3% SCA3/Machado-Joseph disease in our collection. In addition, we demonstrate that the PCR-based Southern blot analysis, with the advantages of sensitivity of PCR and specificity of Southern blot, is a reliable diagnostic method for SCA7 mutation screening. The molecular analysis technique makes possible the quick and accurate diagnosis of SCA7 patients and in the future will hopefully be applied to prenatal screening for SCA7 families.     

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     

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.     

Spinocerebellar ataxia type 12 identified in two Italian families may mimic sporadic ataxia

SCA12 is an autosomal dominant cerebellar ataxia characterized by onset in the fourth decade of life with action tremor of arms and head, mild ataxia, dysmetria, and hyperreflexia. The disease is caused by an expansion of ≥51 CAGs in the 5′ region of the brain‐ specific phosphatase 2 regulatory subunit B‐beta isoform (PPP2R2B) gene. SCA12 is very rare, except for a single ethnic group in India. We screened 159 Italian ataxic patients for SCA12 and identified two families that segregated an expanded allele of 57 to 58 CAGs, sharing a common haplotype. The age at onset, phenotype, and variability of symptoms were compatible with known cases. In one family, the disease was apparently sporadic due to possible incomplete penetrance and/or late age at onset. Our data indicate that SCA12 is also present in Italian patients, and its genetic testing should be applied to both sporadic and familial ataxias. © 2010 Movement Disorder Society     

脊髓小脑共济失调2型、3型患者10例基因突变与临床表型分析

目的探讨脊髓小脑共济失调（SCA）2型、3型患者的基因突变特点及临床表型。方法总结4个SCAs家系的9例患者和1例散发患者的临床表现，对全部患者、43名家系成员及60名健康对照，采用PCR、荧光PCR、毛细管电泳等技术检测分析SCA2、3基因内CAG三核苷酸重复序列的长度及拷贝数。结果3个家系中的6例患者、1例散发患者存在SCA3／MJD（CAG）n扩展突变，CAG重复数为68—75次；1个家系的3例患者存在SCA2（CAG）n扩展突变，CAG重复数为39—41次。两型患者的临床表现有重叠之处，但在发病年龄、病程进展、神经系统受累部位等方面有明显差异。结论SCA3／MJD型与SCA2型在临床表现上存在一定差异性，有助于鉴别和分型，但基因检测是明确诊断的惟一方法。     

Frequency and phenotypes of LRRK2 G2019S mutation in Italian patients with Parkinson's disease.

To evaluate the frequency of the LRRK2 G2019S mutation in Italy, we tested 1,072 probands with Parkinson's disease (PD; 822 sporadic and 250 familial): 20 patients (1.9%) carried the G2019S mutation, 11 patients (1.3%) were sporadic, and 9 (4.3%) had a positive family history. Considering only probands with autosomal dominant inheritance, the G2019S frequency raises to 5.2%. All presented a typical phenotype with variable onset and shared the common ancestral haplotype. Mutation frequency raised from 1.2% in early onset PD to 4.0% in late onset PD.     

Clinical and genetic study of a family with spinocerebellar ataxia type 1 (SCA1) and beta-thalassemia

We report a family affected by autosomal dominant ataxia, in which numerous members also showed microcytosis. Genetic analysis demonstrated a CAG expansion in the SCA1 locus in five members, while all subjects with microcytosis revealed a C-T substitution at codon 39 of the beta-globin gene. A pure cerebellar syndrome with prominent gait ataxia characterized the first stages of the neurological disease. The fully developed disease included additional clinical findings such as dysarthria and dysphagia, and instrumental signs of axonal involvement of the peripheral nerves. Ophthalmoplegia was not observed. The coexistence of hereditary spinocerebellar degeneration and erythropathies or hemoglobinopathies has been previously described. We discuss the possible linkages between these two pathologies.

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Sommario Riportiamo it caso di una famiglia affetta da atassia autosomica dominante, in cui numerosi membri presentavano anche microcitemia. L'analisi genetica dimostrava una espansione CA G net locus SCA1 in cinque membri, mentre tutti i soggetti con microcitemia erano portatori di una sostituzione C-T al codone 39 del gene delta beta-globina. La malattia neurologica era caratterizzata nelle prime fasi da una sindrome cerebellare pura con prevalente atassia delta marcia. Il quadro completo della malatia includeva anche disartria, disfagia e segni di danno assonale ai nervi periferici. Non veniva mai osservata oftalmoplegia. La coesistenza di degenerazione spinocerebellare ereditaria ed eritropatie o emoglobinopatie è già stata descritta precedentemente. Discutiamo i possibili legami tra queste due patologie.

     

Analysis of SCA2 and SCA3/MJD repeats in Parkinson's disease in mainland China: Genetic,clinical, and positron emission tomography findings

To investigate the prevalence and clinical feature(s) of Parkinson's disease (PD) patients with expanded (ATXN2 and MJD1) genes of spinocerebellar ataxia type 2 and 3 (SCA2 and SCA3/MJD) in a mainland Chinese population, CAG triplet repeat expansions of (SCA2 and SCA3/MJD) genes (ATXN2 and MJD1) were analyzed in a cohort of 452 PD patients, including 386 sporadic and 66 familial forms. Striatal dopamine transporter was evaluated in two SCA2 and two SCA3/MJD‐positive family members, an idiopathic PD patient and a healthy control using carbon (C11) [¹¹C]‐radiolabeled‐CFT positron emission tomography (PET). We found two patients in one familial PD (FPD) family (1.5%) and two sporadic PD patients (0.5%) with expanded CAG repeats in the ATXN2 locus, four patients in two FPD families (3%) and another three sporadic PD patients (0.8%) in the MJD1 locus. [¹¹C]‐CFT PET in detected members in SCA2 and SCA3/MJD families showed decrements of ¹¹C‐CFT uptake. These findings suggest that a mutation in SCA2 or SCA3/MJD may be one of the genetic causes of PD. © 2009 Movement Disorder Society     

Masseter reflex in the study of spinocerebellar ataxia type 2 and type 3

In this investigation we assess the utility of the masseter reflex for diagnostic purposes in autosomal dominant cerebellar ataxias. We studied the masseter reflex electrophysiologically in spinocerebellar ataxia type 2 (SCA2, 10 patients) and type 3 (SCA3/MJD, 13 patients). In SCA2, the masseter reflex was abnormal in 9 (90%) patients. In SCA3/MJD, the masseter reflex was normal in all 13 patients. Our findings suggest that the masseter reflex is a reliable test that provides additional data prior to molecular study in the differentiation between SCA2 and SCA3/MJD. Masseter reflex abnormalities in SCA2 patients could be better explained by dysfunction of the mesencephalic trigeminal nucleus/tract. Muscle Nerve, 2009     

A novel LRRK2 mutation in an Austrian cohort of patients with Parkinson's disease.

To investigate the frequency of mutations in the Leucine-Rich Repeat Kinase 2 gene (LRRK2) in a sample of Austrian Parkinson's disease (PD) patients, we sequenced the complete coding region in 16 patients with autosomal dominant PD. Furthermore, we sequenced exons 31, 35, and 41 additionally in 146 patients with idiopathic PD and 30 patients with dementia with Lewy bodies. Furthermore, all 192 patients were screened for 21 putative LRRK2 mutations. While the most common mutation G2019S and the risk variant G2385R were not found in our samples, we detected a novel missense mutation (S973N) in a patient with familial, late-onset and dopa-responsive PD.     

Olfactory performance in spinocerebellar ataxia type 7 patients

A large body of evidence has shown olfactory deficits in many neurodegenerative diseases. However, the nature of the olfactory impairment remains poorly understood partly because the majority of studies have only explored smell identification capabilities. The purpose of the present study was twofold. First we wanted to test if patients with spinocerebellar ataxia type 7 (SCA7), a progressive neurodegenerative disorder characterized by cerebellar ataxia and visual loss, also have olfactory deficits. Secondly, we wanted to test the nature of the olfactory deficits by testing not only the identification level but also olfactory threshold and discrimination. Based on the olfactory dysfunction found in different neurodegenerative diseases and functional neuroimaging data showing cerebellar activation during olfaction, we hypothesized that SCA7 patients would show an olfactory impairment. To test this hypothesis we studied twenty-eight genetically confirmed SCA7 patients and twenty-seven matched controls using the Sniffing Sticks Test and the University of Pennsylvania Smell Identification Test (UPSIT). The results show that SCA7 patients' ability to discriminate and identify odors is significantly impaired, although their odor detection thresholds were at normal levels. These results suggest that SCA7 neurological damage affects olfactory perception but spares the patients' olfactory sensory capabilities.     

Long-term outcome of quetiapine use for psychosis among Parkinsonian patients.

To evaluate the long-term efficacy and tolerability of quetiapine for psychosis among parkinsonian patients, a retrospective analysis of all parkinsonian patients taking quetiapine for psychosis in a single movement disorders center was carried out. Demographic data, including type and severity of psychosis, presence of dementia, treatment response, before and after Unified Parkinson's Disease Rating Scale (UPDRS)-motor scores and Hoehn and Yahr (H&Y) scale were obtained. One hundred six parkinsonian patients with a mean age of 76.6 years were on an average levodopa (L-dopa) dose of 415 mg/d. Seventy-eight of 106 (74%) remained on quetiapine for a mean duration of 15 months at an average dose of 60 mg per day. Eighty-seven (82%) patients had partial or complete resolution of their psychosis whereas 19 (18%) patients had no improvement on quetiapine. Motor worsening was noted in 34 (32%) patients but was uncommonly sufficient to warrant quetiapine discontinuation. More quetiapine non-responders were noted to be demented, delusional, and experienced threatening psychosis but only the presence of dementia remained significant on multivariate analysis (OR = 11.6; 95% CI = 1.4-92.9). Also, patients who developed motor worsening while on quetiapine tended to be more demented (P = 0.07).     

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.     

Sweating in Parkinsonian patients with wearing-off.

Disorders of the autonomic nervous system are common in Parkinson's disease (PD). Earlier studies suggest that some nonmotor symptoms may fluctuate with the motor symptoms, but the possible interrelationship between motor phenomena and sweating has not been studied. The authors measured sweating by using an evaporimeter on three different areas of the body (right hand, left hand, chest) immediately before the morning PD medication (baseline), and thereafter hourly up to 4 hour, in 16 PD patients with wearing-off type of motor fluctuations and in 15 patients without clinical motor fluctuations. The clinical state of the patients was evaluated using the Unified Parkinson's Disease Rating Scale motor score every hour. Sweating increased during the 4-hour follow-up, and reached its maximum level at the time of the highest Unified Parkinson's Disease Rating Scale motor score phase (off-stage) in patients with wearing-off (initially affected hand, P = 0.007; left hand, P = 0.004; right hand, P = 0.034), but in the patients without wearing-off no changes in sweating were observed during the follow-up. Sweating of the left hand (P < 0.001), right hand (P < 0.001), and initially affected hand (P = 0.008) during the whole observation period was significantly higher in patients with motor fluctuations than in those without. The present study shows that sweating fluctuates in conjunction with wearing-off phenomenon.     

Frequency analysis and clinical characterization of different types of spinocerebellar ataxia in Serbian patients.

The relative frequencies of different spinocerebellar ataxias (SCAs) vary widely among different ethnic groups, presumably due to a founder effect. We investigated the relative prevalence of SCA1-3, 6-8, 12, 17; dentate-rubro-pallidoluysian atrophy; and Friedreich's ataxia (FRDA) in Serbian patients with adult-onset (>20 years of age) hereditary and sporadic SCAs, and compared clinical features of patients with genetically confirmed SCAs. A total of 108 patients from 54 families (38 apparently dominant [ADCA] and 16 apparently recessive) with adult-onset hereditary ataxia and 75 apparently sporadic patients were assessed. Of 38 families with ADCA, 13 (34%) were positive for an expansion in an SCA1 and 5 families (13%) for an expansion in an SCA2 allele. In 20 families (53%), no expansions have been identified in any of the analyzed genes. Gaze palsy, spasticity, and hyperreflexia were significantly more common in SCA1, whereas slow saccades, hypotonia, hyporeflexia, and dystonia prevailed in SCA2 patients. Among the 16 families with an apparently recessive mode of ataxia inheritance, 4 (25%) were identified as having the FRDA mutation. Ataxia-causing mutations were identified in 8 (10.6%) of patients with apparently sporadic adult-onset ataxia.