Olfactory heterogeneity in LRRK2 related Parkinsonism

LRRK2 mutations can cause familial and sporadic Parkinson's disease (PD) with Lewy‐body pathology at post‐mortem. Studies of olfaction in LRRK2 are sparse and incongruent. We applied a previously validated translation of the 16 item smell identification test from Sniffin' Sticks (SS‐16) to 14 parkinsonian carriers of heterozygous G2019S LRRK2 mutation and compared with 106 PD patients and 118 healthy controls. The mean SS‐16 score in LRRK2 was higher than in PD (p < 0.001, 95% CI for β = ?4.7 to ?1.7) and lower than in controls (p = 0.007, 95% CI for β = +0.6 to +3.6). In the LRRK2 group, subjects with low scores had significantly more dyskinesia. They also had younger age of onset, longer disease duration, and reported less frequently a family history of PD, but none of these other differences reached significance. Odor identification is diminished in LRRK2 parkinsonism but not to the same extent as in idiopathic PD. © 2010 Movement Disorder Society     

LRRK2 mutations in Parkinson's disease: Confirmation of a gender effect in the Italian population

BackgroundThe relative risk of developing idiopathic PD is 1.5 times greater in men than in women, but an increased female prevalence in LRRK2-carriers has been described in the Ashkenazi Jewish population. We report an update about the frequency of major LRRK2 mutations in a large series of consecutive patients with Parkinson's disease (PD), including extensive characterization of clinical features. In particular, we investigated gender-related differences in motor and non-motor symptoms in the LRRK2 population.Methods2976 unrelated consecutive Italian patients with degenerative Parkinsonism were screened for mutations on exon 41 (G2019S, I2020T) and a subgroup of 1190 patients for mutations on exon 31 (R1441C/G/H). Demographic and clinical features were compared between LRRK2-carriers and non-carriers, and between male and female LRRK2 mutation carriers.ResultsLRRK2 mutations were identified in 40 of 2523 PD patients (1.6%) and not in other primary parkinsonian syndromes. No major clinical differences were found between LRRK2-carriers and non-carriers. We found a novel I2020L missense variant, predicted to be pathogenic. Female gender was more common amongst carriers than non-carriers (57% vs. 40%; p = 0.01), without any gender-related difference in clinical features. Family history of PD was more common in women in the whole PD group, regardless of their LRRK2 status.ConclusionsPD patients with LRRK2 mutations are more likely to be women, suggesting a stronger genetic load compared to idiopathic PD. Further studies are needed to elucidate whether there is a different effect of gender on the balance between genetic and environmental factors in the pathogenesis of PD.     

Clinical expression of LRRK2 G2019S mutations in the elderly

Mutations in the leucine‐rich repeat kinase 2 gene (LRRK2, PARK8) are the most commonly identified monogenic etiology of Parkinson disease (PD). Over‐represented in the Ashkenazi Jewish population, these mutations are transmitted in an autosomal dominant manner with age‐dependent reduced penetrance. The natural history and penetrance of these mutations in the elderly is controversial and inadequately studied. We conducted a nested cohort study in a community‐based aging study (the Einstein Aging Study). Six elderly, initially nonmanifesting carriers (NMC) of the LRKK2 G2019S mutation were identified (average age 82.1 ± 7.0, range 72.7–90.8), and five had available longitudinal data. We matched five noncarrier controls to each NMC and followed them for an average of 4.7 years with annual cognitive and motor examinations. PD was identified in one NMC at age 95 and in no control subjects. The remaining carriers did not differ from controls on motor scores at baseline or follow‐up. The baseline Unified Parkinson's Disease Rating Scale motor subscore (UPDRS‐III) in cases was 6.2 ± 6.9 (range 1–19) and in controls was 4.5 ± 6.6 (1–30), P = 0.6; the mean difference in UPDRS‐III slopes over time between cases and controls was 0.1 ± 1.3 and was not statistically significant. Our data, while limited by a small sample size, show that in LRKK2 G2019S mutation carriers, phenoconversion to PD can occur late in life. However, most NMC have motor decline which is indistinguishable from their age mates, suggesting that the larger subset of elderly NMC is not on the motor trajectory to disease. © 2010 Movement Disorder Society.     

Autonomic dysfunction in parkinsonian LRRK2 mutation carriers

IntroductionThe aim of this study was to compare autonomic function in PD symptomatic carriers of the LRRK2 mutations and idiopathic Parkinson's disease (iPD) patients.Material and methodsWe studied 25 PD patients: 12 with the LRRK2 mutation (6 G2019S and 6 R1441G), and 13 with iPD. All patients underwent blood pressure and heart rate monitoring during head up tilt, Valsalva maneuver and deep breathing, along with recording of sympathetic skin response (SSR) and cardiac MIBG scintigraphy.ResultsThree of the patients with iPD and one of the LRRK2 carriers had orthostatic hypotension. Arterial pressure “overshoot” during phase IV of Valsalva maneuver was less pronounced in patients with iPD. During passive tilt, LRRK2 carries had higher increase of blood pressure than iPD patients MIBG late myocardial/mediastinal uptake ratios were higher in LRRK2 mutation carriers (1.51 ± 0.28 vs 1.32 ± 0.25; p < 0.05).DiscussionCarriers of the LRRK2 mutation had less autonomic impairment than those with iPD as shown by higher cardiac MIBG uptake and a tendency to less impairment of autonomic non-invasive tests. It is important to carry out larger studies comparing the clinical, functional and pathological characteristics of these patients.     

常染色体显性遗传性帕金森病家系临床特征及LRRK2基因分析

目的 研究常染色体显性遗传家族性帕金森病(PD)患者的临床特征及其LRRK2基因突变.方法 对16例常染色体显性遗传家族史的PD患者LRRK2基因的外显子5、13、31、32、35、37、41、48进行测序检测.利用限制性片段长度多态性(RFLP)分析所发现的新突变c.1432 G＞TAsp478Tyr在240例散发性PD患者及214名健康者中的发生频率.结果 常染色体显性遗传家系PD患者与散发性PD患者比较临床特点以晚发为主,首发症状以静止性震颤(9例,56.25%,t=0.558,P=0.679)和动作迟缓(9例,56.25%,t=0.369,P=0.454)最为常见,其次是肌强直(6例,37.50%,t=1.324,P=0.735)和姿势障碍(5例,31.25%,t=2.369,P=0.956),对左旋多巴治疗反应良好,左旋多巴诱导的异动症少见.LRRK2基因突变检测发现6个突变:c.457 T＞C Leu153Leu、c.1432 G＞T Asp478Tyr、c.5457 T＞C Gly1819Gly、c.7153 G＞A Gly2385Arg、IVS31+28 T＞G、IVS37+162 T＞C.其中,c.1432 G＞T Asp478Tyr是未报道过的新突变.在240例散发性PD患者及214名健康者中均未发现有此突变.未发现与PD相关的LRRK2基因突变Arg1441Cys/Gly/His、Arg1514Gln、Tyr1699Cys、Ile2012Thr、Gly2019Ser和Ile2020Thr.结论 常染色体显性遗传性PD患者临床特征表现为典型的PD临床特征,存在LRRK2基因Asp478Tyr和Gly2385Arg突变.Asp478Tyr是未报道过的新突变.     

Clinical and brain imaging characteristics in leucine-rich repeat kinase 2-associated PD and asymptomatic mutation carriers

The objective of this research was to evaluate a possible endophenotype in leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Ten symptomatic LRRK2 patients, 24 sporadic Parkinson's disease patients as well as 10 asymptomatic LRRK2 mutation carriers and 29 matched healthy controls underwent comprehensive clinical assessments with respect to motor and non-motor symptoms. Transcranial sonography and magnetic resonance imaging (voxel-based morphometry [VBM]) were assessed to evaluate morphological imaging characteristics. LRRK2 patients had an earlier onset of motor symptoms and a more benign phenotype of motor and non-motor characteristics compared to sporadic Parkinson's disease patients. However, depression scores were higher in LRRK2 patients. No clinical differences were found regarding motor and non-motor symptoms in asymptomatic LRRK2 mutation carriers in comparison to controls. Transcranial sonography showed hyperechogenicity of the substantia nigra in both patients' cohorts as well as in asymptomatic LRRK2 mutation carriers. Voxel-based morphometry revealed increased gray matter volume of the cerebellum and precentral gyrus in LRRK2 patients and of the cuneus in asymptomatic LRRK2 mutation carriers. In contrast, we found decreased basal ganglia gray matter volume in LRRK2 patients compared to controls. Increased gray matter volume of different anatomical structures associated with motor loops in LRRK2 patients and asymptomatic LRRK2 mutation carriers compared to age-matched sporadic Parkinson's disease patients and controls might indicate compensatory mechanism in LRRK2 mutation carriers due to motor network plasticity not only in the symptomatic stage of the disease but even in the premotor phase. Substantia nigra hyperechogenicity in yet unaffected LRRK2 mutation carriers indicates morphologic alterations in an asymptomatic stage of disease.     

Tremor in Parkinson disease: acute response to oral levodopa

A single blind placebo-controlled study has been performed in order to investigate objectively the acute tremorolytic effect of oral L-Dopa in ten parkinsonians chronically treated with L-Dopa. Finger tremor was assessed by means of a computerized accelerometer method, at rest and during maintenance of a fixed posture. Both resting and postural tremor were significantly influenced by L-Dopa. An “acute test” with oral L-Dopa, especially when different tremor components are investigated, may be useful for identifying objectively parkinsonians whose tremor does not respond to drug therapy or shows a deterioration of drug-responsiveness.

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Sommario Uno studio controllato con placebo è stato condotto su 10 pazienti affetti da morbo di Parkinson idiopatico, in trattamento cronico con L-Dopa, allo scopo di valutare in modo obiettivo l'effetto tremorolitico della L-Dopa. Il tremore è stato valutato alle mani mediante una metodica di accelerometria computerizzata, sia in condizioni di riposo che di postura. In entrambe le condizioni l'effetto tremorolitico della L-Dopa si è rivelato significativo. Un “test acuto” con L-Dopa orale, in particolare con l'esplorazione di componenti diverse del tremore, può risultare utile per una valutazione obiettiva di casi di Parkinson che non rispondano alla terapia farmacologica o che manifestino un deterioramento della risposta alla L-Dopa.

     

LRRK2 G2019S mutation in Parkinson's disease: a neuropsychological and neuropsychiatric study in a large Algerian cohort

A series of 106 patients with isolated or familial Parkinsonism underwent clinical evaluation and genetic testing for the LRRK2 G2019S mutation which was identified in 34/106 patients (32%). Seventy one of them accepted to be evaluated for neuropsychological and neuropsychiatric studies with the aim to compare mutation carriers with non-carriers. For neuropsychological testing, comparisons between LRRK2 G2019S carriers and non-carriers were made after stratification according to the level of education: median and high school versus low level. Memory was investigated with the five words test, 2 novel tests with verbalized visual material dedicated to illiterate patients, the TNI-93 (nine pictures test), The TMA-93 (associative memory test), and digit spans (forward/backward). Cognitive analyse did not show major differences between the two groups of patients. Nevertheless, behavioral abnormalities, mostly depression and hallucinations, were more frequent in the LRRK2 G2019S carriers, suggesting the presence of a greater involvement of the limbic system in these patients. Sleep disorders which were also more common amongst mutation carriers than non-carriers might be related to depression.     

Screening for LRRK2 mutations in patients with Parkinson's disease in Russia: identification of a novel LRRK2 variant

Background and purpose:  Mutations in LRRK2 , encoding leucine-rich repeat kinase 2 (or Dardarin), cause autosomal dominant Parkinson's disease (AdPD) and are also found in sporadic PD (sPD). To investigate the frequency of LRRK2 mutations in a sample of Russian PD patients.
Methods:  We sequenced the complete coding region of LRRK2 in 65 patients with AdPD and in 30 patients with sPD. Furthermore, in 20 patients with AdPD and in 159 patients with sPD we screened several common LRRK2 mutations (G2019S, R1441C/G/H, I2012T and I2020T).
Results:  Five AdPD patients had the LRRK2 G2019S mutation (5.9%, 5/85). In addition, we discovered a novel LRRK2 variant V1613A in a family with a tremor dominant form of AdPD; this variant was not present in controls. We identified two patients with LRRK2 mutations in sPD: one with the G2019S mutation (0.5; 1/189) and another with the previously described R1441C mutation (0,5; 1/189).
Conclusions:  LRRK2 mutations are common amongst patients with PD in Russia. The results also show that the G2019S mutation is the most frequent. We identified one novel mutation in a functional region of LRRK2.     

Neuropathology of Parkinson's disease with the R1441G mutation in LRRK2

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 α‐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. © 2009 Movement Disorder Society     

DNAJC6 mutation causing cranial-onset dystonia with tremor dominant levodopa non-responsive parkinsonism: A novel phenotype

DNAJC6 mutation causes two types of phenotypes: slowly progressive parkinsonism with levodopa response and rapidly progressive parkinsonism with additional manifestations like intellectual disability, epilepsy etc. We report a new phenotype wherein an adolescent girl developed blepharospasm followed by jaw opening, lingual and cervical dystonia followed by tremors of limbs (rest and action) with rigidity, bradykinesia. The dystonia-parkinsonism phenotype has not been described. She had novel homozygous missense mutation in DNAJC6 gene.     

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.     

G2019S LRRK2 mutation in familial and sporadic Parkinson's disease in Russia.

Among mutations associated with autosomal dominant and sporadic Parkinson's disease (PD) the G2019S substitution in the leucine-rich repeat kinase 2 (LRRK2) gene is the most frequently identified. To estimate its frequency in Russia, we analyzed 208 patients with PD from the Northwestern region of Russia. Of these, 51 patients were probands from families with PD compatible with autosomal dominant inheritance. The control group represented 161 subjects without neurological disorders settled in the same region. The frequency of the G2019S mutation was greater in familial PD (2 [3.9%] of 51) than in sporadic PD (1 [0.6%] of 157). In addition, this mutation was found in the proband's father, who also had PD, in 1 PD family, and in 1 carrier without signs of PD at age 40 in another PD family. All carriers were heterozygous for the G2019S mutation and reported the Ashkenazi Jewish origin. The mutation was not found in the control group.