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ABSTRACT: Idiopathic CD4 lymphocytopenia (ICL) is a syndrome described in patients with low counts of CD4 cells and no other causes for immunosuppression. A few cases of progressive multifocal leukoencephalopathy (PML) have been described in association with this entity. There is no effective treatment for any of them, and the clinical course and outcome are unpredictable. We report on a case of ICL with PML and review the literature, trying to identify the clinical features and the prognosis clues associated to these entities together. A 72-year-old man presented with acute onset gait instability that progressed to a severe cerebellar syndrome with cognitive decline. A cranial MRI showed findings consistent with PML, this diagnosis being confirmed by CSF analyses. Absolute number of CD4+ was 242cells/μL. An extensive work-up including HIV tests was negative. Ten cases of PML and ICL have previously been reported. Factors contributing to the different outcomes are unknown. Although an effective treatment does not exist for PML, it has been recently demonstrated in vitro that several 5HT2A-receptor antagonists block the JC virus infection. Our patient greatly improved and remains stable 34months after onset; we describe the potential role of mirtazapine in the treatment of PML.
Journal of the neurological sciences 03/2013; · 2.32 Impact Factor
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Maria Sierra,
Pascual Sánchez-Juan,
María Isabel Martínez-Rodríguez,
Isabel González-Aramburu,
Inés García-Gorostiaga,
María Remedios Quirce,
Enrique Palacio,
José Manuel Carril, José Berciano,
Onofre Combarros,
Jon Infante
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ABSTRACT: We report on the clinical, electrophysiological, and lower-limb musculature MRI findings in a severe demyelinating Guillain-Barré syndrome (GBS) patient with follow-up over 6 months. After 3 weeks of tetraplegia and mechanical ventilation, there was progressive improvement until almost complete recovery. On day 4 after onset, electrophysiological study revealed absent F waves and widespread conduction block. On four further electrophysiological studies on days 12, 19, 45, and 150, there was marked and reversible slow down of motor conduction velocities in upper-limb nerves, and persistent inexcitability of lower-limb nerves. Mild signs of active denervation were recorded in calf and foot muscles as of day 45. On day 39, MRI T2-weighted fat-suppressed images showed patchy hypersignal of variable intensity involving pelvic, thigh, and calf muscles, which disappeared in a second imaging study on day 190; in this study T1-weighted images did not disclose muscle fatty atrophy. We conclude that in severe demyelinating GBS prolonged motor nerve inexcitability should not necessarily be taken as a predictor of poor prognosis, and that MRI is useful in assessing the topography and evolution of muscle denervation.
Journal of Neurology 01/2013; · 3.47 Impact Factor
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Maria Sierra,
Pascual Sánchez-Juan,
María Isabel Martínez-Rodríguez,
Isabel González-Aramburu,
Inés García-Gorostiaga,
María Remedios Quirce,
Enrique Palacio,
José Manuel Carril, José Berciano,
Onofre Combarros,
Jon Infante
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ABSTRACT: OBJECTIVE: To ascertain in a cross-sectional study whether substantia nigra (SN) echogenicity, olfaction, and dopamine transporter (DaT)-SPECT are reliable premotor biomarkers in a cohort of asymptomatic carriers of the LRRK2 G2019S mutation (AsG2019S+). METHODS: These biomarkers were evaluated in 49 AsG2019S+ patients, and we also studied olfaction and SN echogenicity in 29 patients with G2019S-associated Parkinson disease (PD-G2019S), 47 relatives who were noncarriers of the LRRK2 G2019S mutation (AsG2019S-), 50 patients with idiopathic Parkinson disease (iPD), and 50 community controls. RESULTS: Eighty-five percent of unaffected mutation carriers (AsG2019S+) showed pathologic SN hyperechogenicity, with a similar proportion observed among both PD-G2019S and iPD cases, and 41% of AsG2019S- also showing increased SN echogenicity. The proportion of hyposmic individuals was not statistically different in patients with PD-G2019S (50%) and iPD (82%), but hyposmia was significantly less common in both AsG2019S+ (26%) and AsG2019S- (28%). In AsG2019S+ cases, reduced striatal uptake in DaT-SPECT was observed in 43.7%. CONCLUSIONS: Independently of age at examination, the most frequently altered premotor biomarker in LRRK2 G2019S-associated PD was SN hyperechogenicity, whereas abnormal DaT-SPECT predominated in older, unaffected mutation carriers.
Neurology 01/2013; · 8.31 Impact Factor
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ABSTRACT: The aim of this study is to assess the presence of substantia nigra (SN) hypoechogenicity in a cohort of Friedreich's ataxia (FRDA) patients and its possible association with restless syndrome (RLS). Fourteen genetically confirmed FRDA patients and 14 sex- and age-matched healthy controls underwent transcranial sonography examination to evaluate the area of echogenicity of the SN. Both groups were clinically assessed with the essential and additional diagnostic criteria for RLS established by the International RLS Study Group. Ataxia was evaluated using the Scale for the Assessment and Rating of Ataxia. We did not find significant differences between the mean sum area of SN echogenicity in FRDA patients and in controls. Only one patient in the FDRA group and two control subjects showed SN hypoechogenicity. Two out of the 14 FDRA patients and one of the controls fulfilled diagnostic criteria for RLS. The areas of SN echogenicity in the two FRDA patients with RLS were the lowest found in this group. We conclude that our data do not support the notion that SN hypoechogenicity is related to FRDA itself, although it might be associated with RLS.
The Cerebellum 12/2012; · 3.21 Impact Factor
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Neurological Sciences 10/2012; · 1.32 Impact Factor
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Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 09/2012; · 3.12 Impact Factor
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Movement Disorders 06/2012; 27(10):1326. · 4.51 Impact Factor
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Journal of Neurology 04/2012; 254(9):1290-1292. · 3.47 Impact Factor
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Neurological Sciences 02/2012; · 1.32 Impact Factor
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ABSTRACT: Nuclear speckles are essential nuclear compartments involved in the assembly, delivery and recycling of pre-mRNA processing factors, and in the post-transcriptional processing of pre-mRNAs. Oculopharyngeal muscular dystrophy (OPMD) is caused by a small expansion of the polyalanine tract in the poly(A)-binding protein nuclear 1 (PABPN1). Aggregation of expanded PABPN1 into intranuclear inclusions (INIs) in skeletal muscle fibers is the pathological hallmark of OPMD. In this study what we have analyzed in muscle fibers of OPMD patients and in primary cultures of human myoblasts are the relationships between nuclear speckles and INIs, and the contribution of the former to the biogenesis of the latter. While nuclear speckles concentrate snRNP splicing factors and PABPN1 in control muscle fibers, they are depleted of PABPN1 and appear closely associated with INIs in muscle fibers of OPMD patients. The induction of INI formation in human myoblasts expressing either wild type GFP-PABPN1 or expanded GFP-PABPN1-17ala demonstrates that the initial aggregation of PABPN1 proteins and their subsequent growth in INIs occurs at the edges of the nuclear speckles. Moreover, the growing of INIs gradually depletes PABPN1 proteins and poly(A) RNA from nuclear speckles, although the existence of these nuclear compartments is preserved. Time-lapse experiments in cultured myoblasts confirm nuclear speckles as biogenesis sites of PABPN1 inclusions. Given the functional importance of nuclear speckles in the post-transcriptional processing of pre-mRNAs, the INI-dependent molecular reorganization of these nuclear compartments in muscle fibers may cause a severe dysfunction in nuclear trafficking and processing of polyadenylated mRNAs, thereby contributing to the molecular pathophysiology of OPMD. Our results emphasize the potential importance of nuclear speckles as nuclear targets of neuromuscular disorders.
Neurobiology of Disease 01/2012; 46(1):118-29. · 5.40 Impact Factor
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ABSTRACT: Magnetic resonance imaging (MRI) is an extremely useful technique to diagnose muscle denervation. This report presents an acute motor axonal neuropathy (AMAN) patient in whom, over 2 years, serial clinical-electrophysiological evaluation and MRI examination of lower limb musculature were performed. A 74-year-old patient was admitted with a 24-h history of ascending weakness culminating a few days later in flaccid and areflexic tetraplegia, which was followed by progressive improvement except for severe residual paresis of foot flexors/extensors. Electrophysiological studies showed motor nerve conduction abnormalities characteristic of AMAN, and profuse signs of active denervation in foot and lower leg muscles, and to a much lesser degree in the thigh muscles. On MRI, T2- and T2-fat suppressed (T2FS) images showed an early (up to month 2 after onset) and subtle hypersignal of all four lower leg muscle compartments evolving to an extensive and widespread hypersignal (as of month 6). Progressive hypersignal of lower leg musculature on T1-weighted images, indicative of fatty atrophy, was detected as of the first year. Thigh and pelvic musculature exhibited early and reversible hypersignal on T2 and T2FS images. There was good concordance between clinico-electrophysiological and MRI findings. We conclude that serial MRI may be very useful to evaluate the extent of muscle denervation and to assess clinical course in AMAN.
Journal of Neurology 11/2011; 259(6):1111-6. · 3.47 Impact Factor
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Clinical neurology and neurosurgery 11/2011; 114(4):394-5. · 1.30 Impact Factor
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ABSTRACT: The frequency and penetrance of the LRRK2 G2019S mutation varies considerably in different Parkinson disease (PD) populations. This information is essential both for clinical purposes and genetic counseling. The objective of this study was to estimate the prevalence and penetrance of the G2019S mutation of the LRRK2 gene in a small region in northern Spain (Cantabria). The G2019S mutation was tested in 367 consecutive patients with PD attended as outpatients in a tertiary Hospital in Northern Spain, and 126 at-risk family members of probands were also investigated for G2019S mutation and disease status. The gene penetrance was estimated in terms of cumulative age-specific incidence of PD by the Kaplan-Meier method. Thirty-two PD patients (8.7%) carried the G2019S mutation. Penetrance estimation of the G2019S mutation was 2% at 50 years, 12% at 60 years, 26% at 70 years, and 47% at 80 years. The frequency of the G2019S mutation of the LRRK2 gene in PD patients from Cantabria is among the highest reported so far after North African Arabs and Ashkenazi Jews. At the age of 80 years only one-half of G2019S mutation carriers manifest motor symptoms of PD.
Movement Disorders 09/2011; 26(13):2343-6. · 4.51 Impact Factor
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José L Vázquez-Higuera,
Ignacio Mateo,
Pascual Sánchez-Juan,
Eloy Rodríguez-Rodríguez,
Ana Pozueta,
Miguel Calero,
José L Dobato,
Ana Frank-García,
Fernando Valdivieso, José Berciano,
Maria J Bullido,
Onofre Combarros
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ABSTRACT: Tau abnormal hyperphosphorylation and the formation of neurofibrillary tangles in AD brain is the result of upregulation of tau kinases and downregulation of tau phosphatases.
In a group of 729 Spanish late-onset Alzheimer's disease (AD) patients and 670 healthy controls, we examined variations into a set of candidate genes (PPP2CA, PPP2R2A, ANP32A, LCMT1, PPME1 and PIN1) in the tau protein phosphatase-2A (PP2A) pathway, to address hypotheses of genetic variation that might influence AD risk.
There were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by age, gender or APOE ε4 allele.
Our negative findings in the Spanish population argue against the hypothesis that genetic variation in the tau protein phosphatase-2A (PP2A) pathway is causally related to AD risk.
BMC Research Notes 09/2011; 4:327.
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José Luis Vázquez-Higuera,
Ignacio Mateo,
Pascual Sánchez-Juan,
Eloy Rodríguez-Rodríguez,
Ana Pozueta,
Miguel Calero,
José Luis Dobato,
Ana Frank-García,
Fernando Valdivieso, José Berciano,
Maria J Bullido,
Onofre Combarros
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ABSTRACT: Tau abnormal hyperphosphorylation and the formation of neurofibrillary tangles in the Alzheimer's disease (AD) brain is the result of upregulation of tau kinases. In a group of 729 Spanish late-onset AD patients and 670 healthy controls, we examined variations into a set of 20 candidate genes of kinases involved in tau phosphorylation at AD-related sites (PRKACB; CAMK2A; MARK1, 2, 3 and 4; CSNK1D; CDC2; RPS6KB1 and 2; p38α and β; IB1; JNK1, 2 and 3; MEK1 and 2; ERK1 and 2), to address hypotheses of genetic variation that might influence both AD risk and age at disease onset. There was an increased frequency of RPS6KB2 (intron 2, rs917570) minor allele in patients (50%) versus controls (39%) (OR = 1.52; 95% CI 1.30-1.77; p = 1.24 × 10-5 Bonferroni corrected), and the presence of this minor allele was significantly (p = 4.2 × 10-5) associated with a 3-years later onset of AD (mean age 74.1 years) when compared to age at onset of non-minor allele carriers (mean age 71.1 years). In APOE non-ε4 allele carriers, the combined effect of AD-associated risk alleles from the genes of CDC2, RPS6KB1 and 2, p38α, JNK (1, 2 and 3), MEK2, and ERK2 was significantly (p = 0.002) associated with a late-onset (>76 years) of AD. The CDC2 AGC haplotype derived from SNPs in introns 3 (rs2448347), 5 (rs2456772), and 7 (rs1871447) showed a protective effect against AD in APOE non-ε4 allele carriers (permutation p = 1.0 × 10-4) with a frequency of 9% in cases and 15% in controls. Common genetic variation in the tau kinases pathway does underlie individual differences not only in susceptibility to AD but also in disease phenotype (age at disease onset).
Journal of Alzheimer's disease: JAD 08/2011; 27(2):291-7. · 3.74 Impact Factor
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Parkinsonism & Related Disorders 07/2011; 17(6):496-7. · 3.80 Impact Factor
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ABSTRACT: Mild cognitive impairment (MCI) is a heterogeneous clinical entity that comprises the prodromal phase of Alzheimer's disease (Pr-AD). New biomarkers are useful in detecting Pr-AD, but they are not universally available. We aimed to investigate baseline clinical and neuropsychological variables that might predict progression from MCI to AD dementia.
All patients underwent a complete clinical and neuropsychological evaluation at baseline and every 6 months during a two-year follow-up period, with 54 out of 109 MCI patients progressing to dementia (50 of them progressed to AD dementia), and 55 remaining as stable MCI (S-MCI).
A combination of MMSE and California Verbal Learning Test Long Delayed Total Recall (CVLT-LDTR) constituted the best predictive model: subjects scoring above 26/30 on MMSE and 4/16 on CVLT-LDTR had a negative predictive value of 93.93% at 2 years, whereas those subjects scoring below both of these cut-off scores had a positive predictive value of 80.95%.
Pr-AD might be distinguished from S-MCI at baseline using the combination of MMSE and CVLT-LDTR. These two neuropsychological predictors are relatively brief and may be readily completed in non-specialist clinical settings.
BMC Neurology 06/2011; 11:78. · 2.17 Impact Factor
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ABSTRACT: Forefoot pes cavus is a cardinal sign of Charcot-Marie-Tooth disease (CMT). This review is focused on the pathophysiology of pes cavus in CMT1A duplication, which is the most common subtype of the disease. Assessment of foot deformities in CMT1A, their prevalence and proposed mechanisms, and recent contributions of magnetic resonance imaging studies of lower-leg and foot musculature are revised. Special attention is given to papers on foot deformities at initial stages of the disease. We conclude that pes cavus is an early and age-dependent manifestation of CMT1A duplication. Selective denervation of intrinsic foot musculature, particularly of the lumbricals, and not imbalance of lower-leg muscles, seems to be the initial mechanism causing reduced ankle flexibility and forefoot cavus deformity.
Journal of Neurology 05/2011; 258(9):1594-602. · 3.47 Impact Factor
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José Luis Vázquez-Higuera,
Ana Martínez-García,
Pascual Sánchez-Juan,
Eloy Rodríguez-Rodríguez,
Ignacio Mateo,
Ana Pozueta,
Ana Frank,
Fernando Valdivieso, José Berciano,
María J Bullido,
Onofre Combarros
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ABSTRACT: Neurofibrillary tangles, one of the characteristic neuropathological lesions found in Alzheimer's disease (AD) brains, are composed of abnormally hyperphosphorylated tau protein. Tau-tubulin kinase-1 (TTBK1) is a brain-specific protein kinase involved in tau phosphorylation at AD-related sites. We examined genetic variations of TTBK1 by genotyping nine haplotype tagging SNPs (htSNPs) (rs2104142, rs2651206, rs10807287, rs7764257, rs3800294, rs1995300, rs2756173, rs6936397, and rs6458330) in a group of 645 Spanish late-onset AD patients and 738 healthy controls. Using a recessive genetic model, minor allele homozygotes for rs2651206 in intron 1 (OR=0.50, p=0.0003), rs10807287 in intron 5 (OR=0.49, p=0.0002), and rs7764257 in intron 9 (OR=0.57, p=0.023), which are in strong linkage disequilibrium, had a lower risk of developing AD than subjects homozygotes and heterozygotes for the major allele. TTBK1 is a promising new candidate tau phosphorylation-related gene for AD risk.
Neurobiology of aging 03/2011; 32(3):550.e5-9. · 5.94 Impact Factor
