Ludger Schöls

Increased susceptibility to sporadic Parkinson's disease by a certain combined α‐synuclein/apolipoprotein E genotype

Parkinsons disease (PD) is one of the most common neurodegenerative disorders affecting about 1% of Western populations older than age 50. The pathological hallmark of PD are Lewy bodies, that is, intracytoplasmic inclusion bodies in affected neurons of the substantia nigra. Recently, α‐synuclein (α‐SYN) has been identified as the main component of Lewy bodies in sporadic PD, suggesting involvement in neurodegeneration via protein accumulation. The partially overlapping pathology of PD and Alzheimers disease, as well as striking structural similarities of α‐SYN and apolipoprotein E, which is a major risk factor for late‐onset Alzheimers disease, prompted us to investigate the influence of different α‐SYN and apolipoprotein E alleles for developing sporadic PD. We performed association studies in 193 German PD patients and 200 healthy control subjects matched for age, sex, and origin. A polymorphism in the promoter region of the α‐SYN gene (NACP‐Rep1) as well as of the closely linked DNA markers D4S1647 and D4S1628 revealed significant differences in the allelic distributions between PD patients and the control group. Furthermore, the Apoε4 allele but not the Th1/E47 promoter polymorphism of the apolipoprotein E gene was significantly more frequent among early‐onset PD patients (age at onset, <50 years) than in late‐onset PD. Regarding the combination of the Apoε4 allele and allele 1 of the α‐SYN promoter polymorphism, a highly significant difference between the group of PD patients and control individuals has been found, suggesting interactions or combined actions of these proteins in the pathogenesis of sporadic PD. PD patients harboring this genotype have a 12.8‐fold increased relative risk for developing PD during their lives. Ann Neurol 1999;45:611–617

Clinical Features and Neuropathology of Autosomal Dominant Spinocerebellar Ataxia (SCA17)

Autosomal dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders clinically characterized by late‐onset ataxia and variable other manifestations. Genetically and clinically, SCA is highly heterogeneous. Recently, CAG repeat expansions in the gene encoding TATA‐binding protein (TBP) have been found in a new form of SCA, which has been designated SCA17. To estimate the frequency of SCA17 among white SCA patients and to define the phenotypic variability, we determined the frequency of SCA17 in a large sample of 1,318 SCA patients. In total, 15 patients in four autosomal dominant SCA families had CAG/CAA repeat expansions in the TBP gene ranging from 45 to 54 repeats. The clinical features of our SCA17 patients differ from other SCA types by manifesting with psychiatric abnormalities and dementia. The neuropathology of SCA17 can be classified as a “pure cerebellar” or “cerebello‐olivary” form of ataxia. However, intranuclear neuronal inclusion bodies with immunoreactivity to anti‐TBP and antipolyglutamine were much more widely distributed throughout the brain gray matter than in other SCAs. Based on clinical and genetic data, we conclude that SCA17 is rare among white SCA patients. SCA17 should be considered in sporadic and familial cases of ataxia with accompanying psychiatric symptoms and dementia.

Sleep disturbance in spinocerebellar ataxias Is the SCA3 mutation a cause of restless legs syndrome

Objective: To identify and to characterize sleep disturbances in patients with hereditary ataxias. Background: We observed restless legs syndrome (RLS) and impaired sleep as a frequent yet unrecognized symptom in spinocerebellar ataxia type 3 (SCA3). Methods.: A total of 89 patients with genetically defined subtypes of autosomal dominant cerebellar ataxias were investigated for sleep history and neurologic findings according to a standardized protocol. Nerve conduction studies were performed. Sleep was studied by overnight polysomnography in seven patients. Results: RLS was present in 45% of SCA3 patients but is rare in other types of autosomal dominant cerebellar ataxias. RLS was a frequent but not the only cause of sleep impairment in SCA3. Impaired sleep in SCA3 is associated with older age, long-standing disease, and brainstem involvement. RLS tended to be more frequent in patients with clinical signs of polyneuropathy, but RLS was not restricted to patients with peripheral neuropathy. RLS was not observed in healthy members of SCA3 families. Conclusions: RLS is a frequent and treatable cause of disabling sleep disturbance in SCA3. This study provides evidence for the expanded CAG repeat in the SCA3 gene as a molecular factor causing RLS.

Protein surveillance machinery in brains with spinocerebellar ataxia type 3: redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions.

Intracellular aggregates commonly forming neuronal intranuclear inclusions are neuropathological hallmarks of spinocerebellar ataxia type 3 and of other disorders characterized by expanded polyglutamine‐(poly‐Q) tracts. To characterize cellular responses to these aggregates, we performed an immunohistochemical analysis of neuronal intranuclear inclusions in pontine neurons of patients affected by spinocerebellar ataxia type 3, using a panel of antibodies directed against chaperones and proteasome subunits. A subset of the neuronal intranuclear inclusions stained positively for the chaperones Hsp90α and HDJ‐2, a member of the Hsp40 family. Most neuronal intranuclear inclusions were ubiquitin positive, suggesting degradation by ubiquitin‐dependent proteasome pathways. Surprisingly, only a fraction of neuronal intranuclear inclusions were immunopositive for antibodies directed against subunits of the 20S proteolytic core, whereas most inclusions were stained by antibodies directed against subunits of the 11S and 19S regulatory particles. These results suggest that the proteosomal proteolytic machinery that actively degrades neuronal intranuclear inclusions is assembled in only a fraction of pontine neurons in end stage spinocerebellar ataxia type 3. The dissociation between regulatory subunits and the proteolytic core and the changes in subcellular subunit distribution suggest perturbations of the proteosomal machinery in spinocerebellar ataxia type 3 brains.

Familial parkinsonism with synuclein pathology Clinical and PET studies of A30P mutation carriers

Background: The authors identified the second known mutation in the α-synuclein(SNCA) gene, an alanine-to-proline exchange in amino acid position 30 (A30P), that cosegregates with the disease in one German family with autosomal dominantly inherited parkinsonism (ADP). The authors studied carriers of the A30P mutation to compare the phenotype of this mutation with idiopathic PD (IPD) and to assess nigrostriatal dopaminergic function in symptomatic and preclinical mutation carriers. Methods: The pedigree of the A30P family spans five generations with five affected individuals. The authors performed detailed neurologic examinations followed by mutation analysis in 11 living individuals. In three mutation carriers, two individuals with definite PD and one person at risk for PD, they used l-[18]F-fluoro-3,4-dihydroxyphenylalanine (F-DOPA), [11]C-raclopride (RAC), and [18]F-fluorodeoxyglucose (FDG) PET to investigate presynaptic dopaminergic function, dopamine D2 receptors, and cerebral energy metabolism. The authors studied the cognitive functions of carriers of the A30P mutation using neuropsychological screening. Results: PET studies revealed striatal presynaptic dopaminergic alterations consistent with sporadic IPD in two affected family members and no evidence for nigrostriatal dopaminergic dysfunction in one presymptomatic mutation carrier. Neuropsychological testing in four mutation carriers provided evidence for cognitive impairment as a frequent and early symptom of the A30P mutation; this is also supported by regional cerebral energy metabolism alterations in the clinically presymptomatic subject. Conclusions: The phenotype of the A30P mutation in the SNCA gene is similar to that of sporadic IPD, including a high variability of the age at disease onset, ranging from 54 to 76 years. The follow-up of presymptomatic carriers of the A30P mutation may give insight into preclinical disease stages and early manifestations of PD.

The Spastic Paraplegia Rating Scale (SPRS) A reliable and valid measure of disease severity

Objective: To develop and evaluate a clinical Spastic Paraplegia Rating Scale (SPRS) to measure disease severity and progression. Methods: A 13-item scale was designed to rate functional impairment occurring in pure forms of spastic paraplegia (SP). Additional symptoms constituting a complicated form of SP are recorded in an inventory. Two independent patient cohorts were evaluated in a two-step validation procedure. Results: Application of SPRS requires less than 15 minutes and does not require any special equipment, so it is suitable for an outpatient setting. Interrater agreement of SPRS was high (intraclass correlation coefficient = 0.99). Reliability was further supported by high internal consistency (Cronbach α = 0.91). SPRS values were almost normally distributed without apparent floor or ceiling effect. Construct validity was shown by high correlation of SPRS to Barthel Index and the International Cooperative Ataxia Rating Scale (convergent validity) and low correlation to Mini-Mental Status Examination (discriminant validity). Conclusion: The Spastic Paraplegia Rating Scale is a reliable and valid measure of disease severity.

Genetic background of apparently idiopathic sporadic cerebellar ataxia

Abstract Disease-causing mutations have been identified in various entities of autosomal dominant ataxia and in Friedreichs ataxia. However, no molecular pathogenic factor is known to cause idiopathic cerebellar ataxias. We investigated the CAG/CTG trinucleotide repeats causing spinocerebellar ataxia typesxa01, 2, 3, 6, 7, 8 and 12, and the GAA repeat of the frataxin gene in 124 patients apparently suffering from idiopathic sporadic ataxia, including 20 patients with the clinical diagnosis of multiple system atrophy. Patients with a positive family history, a typical Friedreich phenotype, or symptomatic ataxia were excluded. Genetic analyses uncovered the most common Friedreich mutation in 10 patients with an age at onset between 13 and 36xa0years. The SCA6 mutation was present in nine patients with disease onset between 47 and 68xa0years of age. The CTG repeat associated with SCA8 was expanded in three patients. One patient had SCA2 attributable to a de novo mutation from a paternally transmitted, intermediate allele. We did not identify the SCA1, SCA3, SCA7 or SCA12 mutation in idiopathic sporadic ataxia patients. No trinucleotide repeat expansion was detected in the MSA subgroup. This study has revealed the genetic basis in 19% of apparently idiopathic ataxia patients. SCA6 is the most frequent mutation in late onset cerebellar ataxia. The frataxin trinucleotide expansion should be investigated in all sporadic ataxia patients with onset before age 40, even when the phenotype is atypical for Friedreichs ataxia.

Polymorphisms in the interleukin-1 alpha and beta genes and the risk for Parkinson's disease.

Several lines of evidence indicate that immune mechanisms are involved in the pathogenesis of neurodegenerative disorders. Activated immunocompetent cells and inflammatory cytokines are present in affected brain regions in patients with Alzheimers (AD) and Parkinsons disease (PD). For AD biochemical and pathological data are supported by genetic studies identifying risk alleles for polymorphisms in regulatory regions of the interleukin-1 alpha (IL-1 alpha-889) and interleukin-1 beta (IL-1 beta-511) gene, respectively. The partially overlapping pathology and inflammatory reaction pattern between AD and PD led us to investigate these polymorphisms in a large sample of 295 German PD patients and 270 healthy controls. We found T in position -511 in the IL-1 beta gene more frequent in patients compared to controls (chi(2)=4.44, P=0.034). For the IL-1 alpha-889 polymorphism no significant difference between patients and controls was observed.

Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect

Objective: Mutations in SLC2A1, encoding the glucose transporter type 1 (GLUT1), cause a broad spectrum of neurologic disorders including classic GLUT1 deficiency syndrome, paroxysmal exercise-induced dyskinesia (PED, DYT18), and absence epilepsy. A large German/Dutch pedigree has formerly been described as paroxysmal choreoathetosis/spasticity (DYT9) and linked close to but not including the SLC2A1 locus on chromosome 1p. We tested whether 1) progressive spastic paraparesis, in addition to PED, as described in DYT9, and 2) autosomal dominant forms of hereditary spastic paraparesis (HSP) without PED are caused by SLC2A1 defects. Methods: The German/Dutch family and an Australian monozygotic twin pair were clinically (re-)investigated, and 139 index cases with dominant or sporadic HSP in which relevant dominant genes were partially excluded were identified from databanks. SLC2A1 was sequenced in all cases in this observational study and the functional effects of identified sequence variations were tested in glucose uptake and protein expression assays. Results: We identified causative mutations in SLC2A1 in both families, which were absent in 400 control chromosomes, cosegregated with the affection status, and decreased glucose uptake in functional assays. In the 139 index patients with HSP without paroxysmal dyskinesias, we only identified one sequence variation, which, however, neither decreased glucose uptake nor altered protein expression. Conclusions: This study shows that DYT9 and DYT18 are allelic disorders and enlarges the spectrum of GLUT1 phenotypes, now also including slowly progressive spastic paraparesis combined with PED. SLC2A1 mutations were excluded as a cause of HSP without PED in our cohort.

Idebenone in patients with Friedreich ataxia

Friedreich ataxia (FA), the most common form of degenerative ataxia, is thought to be caused by respiratory deficiency due to mitochondrial iron accumulation and oxidative stress. Idebenone, a free-radical scavenger, protects mitochondrial function in in vitro models of FA. In a placebo-controlled crossover trial we studied the effect of idebenone on respiratory function in nine ambulant FA patients. (31)P magnetic resonance spectroscopy demonstrated mitochondrial impairment in vivo in skeletal muscle of all FA patients, but no recovery with idebenone. No effects were seen in clinical scores. Echocardiography did not confirm a preliminary study reporting improvement of FA-associated cardiomyopathy with idebenone.