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

Abstract

Abstract:We report the neuropathological findings in a patient with Parkinson's disease (PD) associated with Basque R1441G-LRRK2/dardarin mutation. The patient was a man with disease onset at 68 years of age, with unilateral rest tremor; the Parkinsonism was well controlled with medication for 15 years. He died at the age of 86, after 18 years of evolution. The neuropathological examination disclosed mild neuronal loss in the substantia nigra pars compacta without a-synuclein, tau, LRRK2, or ubiquitin cytoplasmic inclusions. Lewy bodies and Lewy neurites were absent. This is the first neuropathological study of PD associated with brain with the R1441G mutation in LRRK2. Movement Disorder SocietyKey words: Parkinson's disease; LRRK2; dardarin; neuropathology Pathogenic mutations in the leucine-rich repeated kinase 2 (LRRK2-PARK 8) gene have been identified as the most common currently known cause of familial autosomal dominant Parkinson's disease (PD). 1,2 Patients with PD associated with the LRRK2 mutations have a clinical phenotype similar to other patients with PD without detected mutations. The R1441G-LRRK2/ dardarin mutation is frequent in the Basque country, representing 16% of the familial and 4% of apparently sporadic PD cases. 3 Patients with this mutation belonging to the same family have rather homogenous symptoms and clinical course, but differences are seen between patients with this mutation in different families.The neuropathological changes in patients with PD associated with LRRK2 mutations seem to be heterogeneous. 1 In some cases, the presence of neuronal loss in the substantia nigra (SN) and a-synuclein-positive Lewy bodies (LBs) is consistent with classic PD. In other cases, the neuropathological study shows the presence of nonspecific neuronal loss with ubiquitinreactive cytoplasmic and nuclear inclusions, tau pathology reminiscent of progressive supranuclear palsy, or pure nigral degeneration without specific a-synuclein, tau, or ubiquitin inclusions. 1 We report here a patient with the R1441G-LRRK2/ dardarin mutation with neurological symptoms consistent with classic PD. The neuropathological examination disclosed nonspecific nigral degeneration in the SN without a-synuclein, tau, LRRK2, or ubiquitin inclusions. CASE REPORTA 69-year-old man presented with a 1-year history of rest tremor in his right hand. Two years before, he had an angina episode and since then had been taking 100 mg aspirin daily. Although his family history for PD was negative, the sister of the patient explained that their mother, of Basque origin (Durango-Bizcay), had suffered from upper limb tremor and clumsiness at an older age. The mother did not know their origin because she had been brought up in an orphanage. The father of the patient was of Castilian origin. The patient had no children and had one sister and one Vol. 24, No. 13, 2009, pp. 1998-2019 2009 Movement Disorder Society brother without neurological symptoms at the age of 83 and 73 years, respectively, and so they were not tested for the mutation...

Preclinical and clinical neural network changes in SCA2 parkinsonism

“…Sequence analyses suggested that the normal allele contained two CAA interruptions and displayed a configuration of (CAG) 8 CAA(CAG) 4 CAA(CAG) 8 , while the expanded alleles only contained a reserved 3’-CAA interruption and displayed a configuration as (CAG) n CAA(CAG) 8 . Two patients had participated in a previous study, and had been examined with [ 11 C]-CFT (2-b-carbomethoxy-3b-(4-fluorophenyl)tropane) positron emission tomography (PET) showing bilateral decrement of 11 C-CFT uptake in the stratum [16]. …”

“…Additionally, PET results indicated that the patients had dopaminergic deficits [16]. Therefore, it is logical to consider that these asymptomatic SCA2 mutation carriers were at the preclinical stage of parkinsonism and provide a good dataset to investigate neural modulations at preclinical and clinical stage.…”

“…A striatal dopaminergic deficit has been demonstrated in both familial parkinson patients and asymptomatic carriers with SCA2 mutations [16,17]. In the current study, we used the asymptomatic and symptomatic SCA2 mutation carriers to investigate the resting state functional connectivity of brain networks in the preclinical and clinical stages.…”

Analysis of the GGGGCC Repeat Expansions of the C9orf72 Gene in SCA3/MJD Patients from China

“…However, the clinical syndromes from the varied mutations may be strikingly similar to each other [2, 3]. Previous study [4–6] suggested that the CAG repeats mutation in SCA2 or SCA3/Machado-Joseph disease (MJD) may be associated with Parkinsonism. A recent study [7] showed a common molecular mechanism between SCA3/MJD and ALS due to the similar ubiquitination and degradation of ataxia-3 and SOD.…”

Large-scale assessment of polyglutamine repeat expansions in Parkinson disease

“…Previous clinical and pathologic findings emphasize the need to evaluate the significance of polyglutamine repeat expansions of these genes in PD worldwide. [4][5][6][7][8][9] Most studies performed to date, including this study, are biased by case selection at specialist movement disorders clinics. However, to get a better estimate of the frequency of repeat expansions in such a setting, their relative contribution to disease worldwide, we performed a large multicenter study with members of the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium.…”