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2.
Neurogenetics ; 14(1): 11-22, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23334463

RESUMEN

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41% of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.


Asunto(s)
Enfermedades de los Ganglios Basales/genética , Calcinosis/genética , Mutación , Enfermedades Neurodegenerativas/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/genética , Adulto , Anciano , Secuencia de Aminoácidos , Estudios de Cohortes , Análisis Mutacional de ADN , Familia , Femenino , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Modelos Biológicos , Datos de Secuencia Molecular , Mutación/fisiología , Estudios Retrospectivos
3.
Mov Disord ; 25(5): 615-22, 2010 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-20175186

RESUMEN

Visual Hallucinations (VH) are among the core features of Dementia with Lewy Bodies (DLB), but are also very frequent in demented patients with Parkinson's Disease (PDD). The purpose of this study was to investigate the pattern of gray matter and cognitive impairment underlying VH in DLB and PDD. We applied voxel-based morphometry and behavioral assessment to 12 clinically diagnosed DLB patients and 15 PDD patients. Subjects with VH showed greater gray matter loss than non-hallucinators, specifically in the right inferior frontal gyrus (BA 45) in the DLB patients and in the left orbitofrontal lobe (BA 10) in the PDD patients. Comparing the two subgroups with VH, DLB patients had greater decrease of the bilateral premotor area (BA 6) than PDD patients. Furthermore, decreased volume in associative visual areas, namely left precuneus and inferior frontal lobe, correlated with VH in the DLB but not in PDD patients. VH were related to impaired verbal fluency, inhibitory control of attention and visuoperception in the DLB group and to visual memory in the PDD group. In conclusion, DLB and PDD patients with VH had more frontal gray matter atrophy than non-hallucinators, the impairment being greater in the DLB group. The patterns of structural and functional correlations were different in both pathologies.


Asunto(s)
Lóbulo Frontal/fisiopatología , Alucinaciones/etiología , Alucinaciones/patología , Enfermedad por Cuerpos de Lewy/complicaciones , Enfermedad de Parkinson/complicaciones , Anciano , Anciano de 80 o más Años , Análisis por Conglomerados , Trastornos del Conocimiento/etiología , Femenino , Lóbulo Frontal/patología , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estadística como Asunto
4.
Mov Disord ; 24(12): 1740-6, 2009 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-19569130

RESUMEN

There is controversy regarding whether Dementia with Lewy Bodies (DLB) and Parkinson's disease with dementia (PDD) may or not be different manifestations of the same disorder. The purpose of the present study was to investigate possible correlations between brain structure and neuropsychological functions in clinically diagnosed patients with DLB and PDD. The study sample consisted of 12 consecutively referred DLB patients, 16 PDD patients, and 16 healthy control subjects recruited from an outpatient setting, who underwent MRI and neuropsychological assessment. Voxel-based morphometry results showed that DLB patients had greater gray matter atrophy in the right superior frontal gyrus, the right premotor area and the right inferior frontal lobe compared to PDD. Furthermore, the anterior cingulate and prefrontal volume correlated with performance on the Continuous Performance Test while the right hippocampus and amygdala volume correlated with Visual Memory Test in the DLB group. In conclusion, DLB patients had more fronto-temporal gray matter atrophy than PDD patients and these reductions correlated with neuropsychological impairment.


Asunto(s)
Encéfalo/patología , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/patología , Enfermedad por Cuerpos de Lewy/complicaciones , Enfermedad de Parkinson/complicaciones , Estadística como Asunto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Mapeo Encefálico , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/patología , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Enfermedad de Parkinson/patología , Escalas de Valoración Psiquiátrica , Estadísticas no Paramétricas
5.
PLoS One ; 10(7): e0132368, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26177462

RESUMEN

OBJECTIVE: In idiopathic Parkinson disease (IPD) sleep disorders are common and may antedate the onset of parkinsonism. Based on the clinical similarities between IPD and Parkinson disease associated with LRRK2 gene mutations (LRRK2-PD), we aimed to characterize sleep in parkinsonian and nonmanifesting LRRK2 mutation carriers (NMC). METHODS: A comprehensive interview conducted by sleep specialists, validated sleep scales and questionnaires, and video-polysomnography followed by multiple sleep latency test (MSLT) assessed sleep in 18 LRRK2-PD (17 carrying G2019S and one R1441G mutations), 17 NMC (11 G2019S, three R1441G, three R1441C), 14 non-manifesting non-carriers (NMNC) and 19 unrelated IPD. RESULTS: Sleep complaints were frequent in LRRK2-PD patients; 78% reported poor sleep quality, 33% sleep onset insomnia, 56% sleep fragmentation and 39% early awakening. Sleep onset insomnia correlated with depressive symptoms and poor sleep quality. In LRRK2-PD, excessive daytime sleepiness (EDS) was a complaint in 33% patients and short sleep latencies on the MSLT, which are indicative of objective EDS, were found in 71%. Sleep attacks occurred in three LRRK2-PD patients and a narcoleptic phenotype was not observed. REM sleep behavior disorder (RBD) was diagnosed in three LRRK2-PD. EDS and RBD were always reported to start after the onset of parkinsonism in LRRK2-PD. In NMC, EDS was rarely reported and RBD was absent. When compared to IPD, sleep onset insomnia was more significantly frequent, EDS was similar, and RBD was less significantly frequent and less severe in LRRK2-PD. In NMC, RBD was not detected and sleep complaints were much less frequent than in LRRK2-PD. No differences were observed in sleep between NMC and NMNC. CONCLUSIONS: Sleep complaints are frequent in LRRK2-PDand show a pattern that when compared to IPD is characterized by more frequent sleep onset insomnia, similar EDS and less prominent RBD. Unlike in IPD, RBD and EDS seem to be not markers of the prodromal stage of LRRK2-PD.


Asunto(s)
Mutación/genética , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Trastornos del Sueño-Vigilia/complicaciones , Trastornos del Sueño-Vigilia/genética , Adulto , Demografía , Electromiografía , Femenino , Heterocigoto , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/enzimología , Polisomnografía , Trastorno de la Conducta del Sueño REM/complicaciones , Trastorno de la Conducta del Sueño REM/genética , Síndrome de las Piernas Inquietas/complicaciones , Síndrome de las Piernas Inquietas/genética , Trastornos del Sueño-Vigilia/enzimología
6.
Parkinsonism Relat Disord ; 21(10): 1170-6, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26306001

RESUMEN

BACKGROUND: Substantia nigra hyperechogenicity (SN+) has been proposed as a risk marker of Parkinson's disease (PD). Asymptomatic LRRK2 mutation carriers (aLRRK2+), at high risk for developing PD, provide an opportunity for the study of preclinical biomarkers. OBJECTIVE: To assess SN echogenicity and other echographic features in LRRK2 G2019S carriers and their clinical and imaging correlates. METHODS: Transcranial sonography was performed in 26 LRRK2 G2019S PD patients, 50 first-degree relatives, 31 idiopathic PD (IPD) patients and 26 controls. SN echogenicity and other echographic features were assessed in all study subjects. Dopamine transporter imaging (DAT-SPECT) was performed in 29 first-degree relatives. RESULTS: 75% of the LRRK2-PD and 87.5% of the IPD showed SN+ (p = 0.087). aLRRK2+ had a higher frequency of SN+ than non carriers (58.3% vs. 25%, p = 0.039) and controls (58.3% vs. 12.5%; p = 0.002) and had a larger area of SN echogenicity than non carriers (p = 0.030) and controls (p < 0.001). The width of the third ventricle was significantly lower in LRRK2-PD than in IPD (1.9 mm [1.38; 2.75] vs. 3.0 mm [2.3; 5.3]; p = 0.003). Four out of 5 (80%) of the aLRRK2+ with an abnormal DAT-SPECT and four of the 5 (80%) of those with REM sleep behaviour disorder (RBD) had SN+. CONCLUSIONS: SN+ is very frequent in LRRK2-PD and aLRRK2+. Most aLRRK2 with possible surrogate markers of PD such as abnormal DAT-SPECT or RBD, also had SN+, which supports that this echofeature might be a marker of PD in these asymptomatic population.


Asunto(s)
Heterocigoto , Mutación , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Sustancia Negra/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/análisis , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Femenino , Marcadores Genéticos , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único , Ultrasonografía Doppler Transcraneal , Adulto Joven
7.
Neurochem Int ; 63(1): 42-6, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23619397

RESUMEN

The molecular interaction between adenosine A2A and dopamine D2 receptors (A2ARs and D2Rs, respectively) within an oligomeric complex has been postulated to play a pivotal role in the adenosine-dopamine interplay in the central nervous system, in both normal and pathological conditions (e.g. Parkinson's disease). While the effects of A2AR challenge on D2R functioning have been largely studied, the reverse condition is still unexplored, a fact that might have impact in therapeutics. Here, we aimed to examine in a real-time mode the D2R-mediated allosteric modulation of A2AR binding when an A2AR/D2R oligomer is established. Thus, we synthesized fluorescent A2AR agonists and evaluated, by means of a flow cytometry homogeneous no-wash assay and a real-time fluorescence resonance energy transfer (FRET)-based approach, the effects on A2AR binding of distinct antiparkinsonian drugs in current clinical use (i.e. pramipexole, rotigotine and apomorphine). Our results provided evidence for the existence of a differential D2R-mediated negative allosteric modulation on A2AR agonist binding that was oligomer-formation dependent, and with apomorphine being the best antiparkinsonian drug attenuating A2AR agonist binding. Overall, the here-developed methods were found valid to explore the ability of drugs acting on D2Rs to modulate A2AR binding, thus serving to facilitate the preliminary selection of D2R-like candidate drugs in the management of Parkinson's disease.


Asunto(s)
Agonistas del Receptor de Adenosina A2/metabolismo , Biopolímeros/metabolismo , Receptor de Adenosina A2A/metabolismo , Receptores de Dopamina D2/fisiología , Citometría de Flujo , Transferencia Resonante de Energía de Fluorescencia , Células HEK293 , Humanos , Unión Proteica , Receptores de Dopamina D2/metabolismo
8.
Case Rep Neurol Med ; 2012: 278140, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22953088

RESUMEN

Forehead tremor has only been reported in two patients with essential tremor, one with rhythmic tremor and the other with dystonic tremor. We report 4 new patients with essential tremor who present a 4-6 Hz frontal tremor registered by electromyography and unusual features like frontal tremor preceding limb tremor or unilateral involvement. Frontal tremor is present in some patients with essential tremor, sometimes preceding limb tremor. Treatment with botulinum toxin may be useful.

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