11. |
- Puschmann, Andreas, et al.
(författare)
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Diagnosis and Treatment of Common Forms of Tremor
- 2011
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Ingår i: Seminars in Neurology. - : Georg Thieme Verlag KG. - 0271-8235 .- 1098-9021. ; 31:1, s. 65-77
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Tidskriftsartikel (refereegranskat)abstract
- Tremor is the most common movement disorder presenting to an outpatient neurology practice and is defined as a rhythmical, involuntary oscillatory movement of a body part. The authors review the clinical examination, classification, and diagnosis of tremor. The pathophysiology of the more common forms of tremor is outlined, and treatment options are discussed. Essential tremor is characterized primarily by postural and action tremors, may be a neurodegenerative disorder with pathologic changes in the cerebellum, and can be treated with a wide range of pharmacologic and nonpharmacologic methods. Tremor at rest is typical for Parkinson's disease, but may arise independently of a dopaminergic deficit. Enhanced physiologic tremor, intention tremor, and dystonic tremor are discussed. Further differential diagnoses described in this review include drug- or toxin-induced tremor, neuropathic tremor, psychogenic tremor, orthostatic tremor, palatal tremor, tremor in Wilson's disease, and tremor secondary to cerebral lesions, such as Holmes' tremor ( midbrain tremor). An individualized approach to treatment of tremor patients is important, taking into account the degree of disability, including social embarrassment, which the tremor causes in the patient's life.
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12. |
- Puschmann, Andreas, et al.
(författare)
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First neuropathological description of a patient with Parkinson's disease and LRRK2 p.N1437H mutation.
- 2012
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Ingår i: Parkinsonism & Related Disorders. - : Elsevier BV. - 1873-5126 .- 1353-8020. ; 18:4, s. 332-338
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Tidskriftsartikel (refereegranskat)abstract
- The c.4309A>C mutation in the LRRK2 gene (LRRK2 p.N1437H) has recently been reported as the seventh pathogenic LRRK2 mutation causing monogenic Parkinson's disease (PD). So far, only two families worldwide have been identified with this mutation. By screening DNA from seven brains of PD patients, we found one individual with seemingly sporadic PD and LRRK2 p.N1437H mutation. Clinically, the patient had levodopa-responsive PD with tremor, and developed severe motor fluctuations during a disease duration of 19 years. There was severe and painful ON-dystonia, and severe depression with suicidal thoughts during OFF. In the advanced stage, cognition was slow during motor OFF, but there was no noticeable cognitive decline. There were no signs of autonomic nervous system dysfunction. Bilateral deep brain stimulation of the subthalamic nucleus had unsatisfactory results on motor symptoms. The patient committed suicide. Neuropathological examination revealed marked cell loss and moderate alpha-synuclein positive Lewy body pathology in the brainstem. There was sparse Lewy pathology in the cortex. A striking finding was very pronounced ubiquitin-positive pathology in the brainstem, temporolimbic regions and neocortex. Ubiquitin positivity was most pronounced in the white matter, and was out of proportion to the comparatively weaker alpha-synuclein immunoreactivity. Immunostaining for tau was mildly positive, revealing non-specific changes, but staining for TDP-43 and FUS was entirely negative. The distribution and shape of ubiquitin-positive lesions in this patient differed from the few previously described patients with LRRK2 mutations and ubiquitin pathology, and the ubiquitinated protein substrate remains undefined.
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13. |
- Puschmann, Andreas
(författare)
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Genetics of Parkinson's
- 2012
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Ingår i: Life with Parkinson's. Accurate Diagnosis, Treatment and Care. ; , s. 88-90
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Bokkapitel (populärvet., debatt m.m.)
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14. |
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15. |
- Puschmann, Andreas, et al.
(författare)
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Genotype-Phenotype Correlations in Parkinson Disease
- 2014
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Ingår i: Movement Disorders: Genetics and Models, 2nd Edition. - 9780124051959 - 9780124055162 ; , s. 259-285
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Bokkapitel (refereegranskat)abstract
- Mutations in four autosomal dominant (SNCA, LRRK2, VPS35, EIF4G1) and three recessive genes (PARK2, PINK1, PARK7/DJ1) are known to cause Parkinson disease (PD). This chapter describes the clinical and pathological phenotypes associated with mutations in these genes. We systematically reviewed the phenotypes associated with all known pathogenic mutations in the dominant genes. SNCA point mutations and genomic multiplications cause a disorder with akinetic-rigid Parkinsonism, dysautonomia, cognitive decline, myoclonus, and pronounced alpha-synuclein pathology. LRRK2 mutations cause tremor-dominant or akinetic-rigid Parkinsonism with variable pathology. Our knowledge about the newly described genes VPS35 and EIF4G1 is still limited. Homozygous or compound heterozygous mutations in the recessive PD genes cause Parkinsonism with an early or very-early onset, but many different mutations are found in these genes and genotype-phenotype correlations are based on low numbers of patients per mutation. Homozygous mutations in GBA may cause Parkinsonism, usually in patients who have Gaucher disease, whereas heterozygous GBA mutations are genetic risk factors for PD. The monogenic forms of PD represent distinct subtypes of this heterogeneous disorder.
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16. |
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17. |
- Puschmann, Andreas
(författare)
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Heredity in Parkinson's disease. From rare mutations to common genetic risk factors.
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This study investigated genetic causes of Parkinson's disease (PD) and parkinsonism in southern Sweden. The extensive Lister Family with parkinsonism caused by duplications and triplications of the gene for alpha-synuclein (SNCA) was studied. Clinical, genetic and genealogical data were compiled and evaluated. Thirty-five family members with parkinsonism were identified. They share a characteristic clinical subtype of parkinsonism with marked dysfunction of the autonomic nervous system, behavioral changes and cognitive decline. The clinical phenotype, heredity and genetic background of 132 probands from Southern Sweden with PD or parkinsonism was examined. The SNCA, LRRK2, EIF4G1, VPS35, PINK1, ATXN2 and ATXN3 genes were analyzed in all probands; the PARKIN, PINK1 and DJ1 genes were tested in a subgroup of 23 patients with young onset or marked heredity. DNA from the brain tissue of 7 patients with parkinsonism was also analyzed. Common genetic risk factors in DNA samples collected within this study were analyzed in collaboration with other research groups. Gene screening identified two rare causative mutations, SNCA A53T and LRRK2 N1437H. An additional patient was compound heterozygous for PARKIN R275W and R275Q mutations. Detailed information on their clinical picture is presented. We present the first neuropathological description of a patient with PD and LRRK2 N1437H mutation, showing pronounced ubiquitin and moderate alpha-synuclein pathology. A heterozygous PINK1 G411S mutation was present in two PD patients but showed no clear co-segregation with the disease in their families. Screening of 1,107 patients and controls as well as meta-analysis of published reports from 7,800 individuals revealed that the PINK1 G411S mutation is a rare risk variant with a relatively large effect size (odds ratios 4.06-8.42). One multicenter study confirmed that common variants in the SNCA and MAPT genes modify PD risk, and was large enough to refute gene-gene interaction between the MAPT and SNCA variants. These results suggest that specific mutations in PD-genes cause characteristic disease subtypes. Despite extensive screening and a high proportion of familial cases, known pathogenic mutations could only explain a small proportion of parkinsonism in this cohort. This may indicate that mutations causing parkinsonism in the Scandinavian population remain to be discovered. Alternatively, familial clustering and sporadic occurrence of PD may be explained by combinations of rare variants with relatively large effect size, such as PINK1 G411S.
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18. |
- Puschmann, Andreas, et al.
(författare)
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Human leukocyte antigen variation and Parkinson's disease.
- 2011
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Ingår i: Parkinsonism & Related Disorders. - : Elsevier BV. - 1873-5126 .- 1353-8020. ; 17, s. 376-378
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Tidskriftsartikel (refereegranskat)abstract
- A role for the immune system in the pathogenesis of Parkinson's Disease (PD) has previously been suggested. A recent genome-wide association (GWA) study identified an association between one single nucleotide polymorphism (SNP) in the human leucocyte antigen (HLA) region (HLA-DRA rs3129882) and PD in a population of American patients with European ancestry. In that study, the minor rs3129882 allele (G) was associated with an increased risk of PD under an additive model. Due to the increased likelihood of obtaining false positive results in GWA studies compared to studies conducted based on a hypothesis-driven approach, repeated validation of findings from GWA studies are necessary. Herein, we evaluated the association between rs3129882 and PD in three different Caucasian patient-control series (combined 1313 patients and 1305 controls) from the US, Ireland, and Poland. We observed no association (OR: 0.96, P = 0.50) between rs3129882 and PD when analyzing our data under an additive or dominant model. In contrast, when examined under a recessive model, the GG genotype was observed to be protective in the Irish (OR: 0.55, P = 0.008), Polish (OR: 0.67, P = 0.040) and combined (OR: 0.75, P = 0.006) patient-control series. In view of these diverging results, the exact role of genetic variation at the HLA region and susceptibility to PD remains to be resolved.
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19. |
- Puschmann, Andreas J., et al.
(författare)
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Familial late-onset focal dystonia in an African American family
- 2010
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Ingår i: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 68:Suppl. S14, s. 69-69
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Konferensbidrag (refereegranskat)abstract
- Recent studies of THAP1 (DYT6) have pointed out that late-onset focal dystonia can have a genetic basis. Familial late-onset primary dystonia has not been described in African- Americans. Six members of an African American family were affected by focal or segmental dystonia with a mean age at onset of 47 years (range, 45-50). Two additional individuals with milder clinical signs were classified as probably affected. Clinical phenotypes included cervical, laryngeal and handforearm (writer's cramp) dystonia, following an autosomal dominant mode of inheritance. TOR1A (DYT1) and THAP1 (DYT6) were screened for sequence variants. There were no abnormalities in TOR1A. A novel THAP1 sequence variant (c.-237-3G>T) was found in both affected and unaffected family members and did not co-segregate with dystonia. This variant was also found in 1/212 African American control alleles. Another variant at the same site (c.-237-3G>A) was found in 2/212 African American control alleles and one African American subject with laryngeal dystonia (1/84 alleles). Therefore, these variants are unlikely to be pathogenic. Familial late-onset primary dystonia does occur in non-Caucasian populations. Future studies of THAP1 and other dystonia genes must take genetic background into consideration.
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20. |
- Puschmann, Andreas
(författare)
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Monogenic Parkinson's disease and parkinsonism: Clinical phenotypes and frequencies of known mutations.
- 2013
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Ingår i: Parkinsonism & Related Disorders. - : Elsevier BV. - 1873-5126 .- 1353-8020. ; 19:4, s. 407-415
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Forskningsöversikt (refereegranskat)abstract
- Mutations in seven genes are robustly associated with autosomal dominant (SNCA, LRRK2, EIF4G1, VPS35) or recessive (parkin/PARK2, PINK1, DJ1/PARK7) Parkinson's disease (PD) or parkinsonism. Changes in a long list of additional genes have been suggested as causes for parkinsonism or PD, including genes for hereditary ataxias (ATXN2, ATXN3, FMR1), frontotemporal dementia (C9ORF72, GRN, MAPT, TARDBP), DYT5 (GCH1, TH, SPR), and others (ATP13A2, CSF1R, DNAJC6, FBXO, GIGYF2, HTRA2, PLA2G6, POLG, SPG11, UCHL1). This review summarizes the clinical features of diseases caused by mutations in these genes, and their frequencies. Point mutations and multiplications in SNCA cause cognitive or psychiatric symptoms, parkinsonism, dysautonomia and myoclonus with widespread alpha-synuclein pathology in the central and peripheral nervous system. LRRK2 mutations may lead to a clinical phenotype closely resembling idiopathic PD with a puzzling variety in neuropathology. Mutations in parkin/PARK2, PINK1 or DJ1/PARK7 may cause early-onset parkinsonism with a low risk for cognitive decline and a pathological process usually restricted to the brainstem. Carriers of mutations in the other genes may develop parkinsonism with or without additional symptoms, but rarely a disease resembling PD. The pathogenicity of several mutations remains unconfirmed. Although some mutations occur with high frequency in specific populations, worldwide all are very rare. The genetic cause of the majority of patients with sporadic or hereditary PD remains unknown in most populations. Clinical genetic testing is useful for selected patients. Testing strategies need to be adapted individually based on clinical phenotype and estimated frequency of the mutation in the patient's population.
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