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Pedro Gonzalez-Alegre

Publications and source records attributed to Pedro Gonzalez-Alegre.

13 recordsLinked to original sources
PubMed2006

Monomelic parkinsonian tremor caused by contralateral substantia nigra stroke.

Patients with Parkinson's disease have been frequently classified by their most prominent symptoms into tremor-predominant and akinetic/rigid variants. A few pathological studies have suggested that these different phenotypes represent topographical differences in nigral pathology. A patient is described in whom a medial substantia nigra stroke led to contralateral lower extremity parkinsonian tremor, providing a clinical-pathological correlation of this tremor, indicating a somatotopic organization of the substantia nigra and supporting the central generator hypothesis of parkinsonian tremor.

Adolescent↗
PubMed2006

Delineation of the motor disorder of Lesch-Nyhan disease.

Lesch-Nyhan disease (LND) is caused by deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Affected individuals exhibit over-production of uric acid, along with a characteristic neurobehavioural syndrome that includes mental retardation, recurrent self-injurious behaviour and motor disability. Prior studies involving relatively small numbers of patients have provided different conclusions on the nature of the motor disorder. The current study includes the results of a multi-centre international prospective study of the motor disorder in the largest cohort of patients studied to date. A total of 44 patients ranging from 2 to 38 years presented a characteristic motor syndrome that involved severe action dystonia superimposed on baseline hypotonia. Although some patients also displayed other extrapyramidal or pyramidal signs, these were always less prominent than dystonia. These results are compared with a comprehensive review of 122 prior reports that included a total of 254 patients. Explanations for the differing observations available in the literature are provided, along with a summary of how the motor disorder of LND relates to current understanding of its pathophysiology involving the basal ganglia.

Adolescent↗
PubMed2006

Isolated high-frequency jaw tremor relieved by botulinum toxin injections.

Jaw tremor can be seen as a component of various neurological disorders such as essential tremor, Parkinson's disease, dystonia, branchial myoclonus, hereditary geniospasm, task-specific tremor, and Whipple's disease, as well as in normal situations such as shivering, and subclinical physiological jaw tremor. In most of these conditions, the jaw tremor is usually associated with tremor or other abnormal involuntary movements affecting additional body parts, and its frequency is lower than 12 Hz. Schrag and colleagues reported a patient with a high-frequency idiopathic jaw tremor, and they speculated it could be related to orthostatic tremor affecting the masseter muscles. We encountered a similar patient with intermittent rapid focal jaw tremor that was successfully treated with botulinum toxin injections to the masseters.

Adult↗
PubMed2006

Silencing neurodegenerative disease: bringing RNA interference to the clinic.

RNA interference (RNAi) is a recently described conserved biological pathway where non-coding RNAs suppress the expression of specific genes. Research efforts in the RNAi field aim to gain a better understanding of how its underlying machinery is orchestrated, to define the biological role of this conserved pathway, determine how to effectively manipulate RNAi in the laboratory and to integrate all this knowledge to develop novel therapies for human disease. This review summarizes the advances in the design of therapeutic RNAi for neurodegenerative diseases and discusses some of the experimental steps required to bring this therapy to human clinical trials.

Animals↗
PubMed2006

Clinical characteristics of childhood-onset (juvenile) Huntington disease: report of 12 patients and review of the literature.

Whereas adult-onset Huntington disease is a well-characterized clinical entity, childhood-onset cases have not received as much attention. In this report, the clinical, demographic, and genetic characteristics in 12 patients with childhood-onset Huntington disease are presented and compared with data in the literature. The patients were divided into two groups based on age at onset of symptoms (< 10 or > or = 10 years old). The majority of patients had onset of symptoms before 10 years of age and most at or below 5 years of age. The delay in diagnosis was longer in those with earlier onset of symptoms. Inheritance was paternal in all patients with onset beyond 10 years of age. We found a preponderance of male patients in the younger age at onset group and of female patients in the older age at onset group. The most frequent heralding symptom was cognitive decline in the group with earlier onset and oropharyngeal dysfunction in the later-onset group. Seizures occurred only in the younger age at onset group. Chorea was not a presenting sign but developed later in the course of the disease and, with dystonia, was more prevalent in the early age at onset group, whereas rigidity and bradykinesia were more prevalent in the older age at onset group. Patients in both groups developed gait, cognitive, and behavioral disorders at some point during the course of the disease. Furthermore, a slow and steady decline in IQ was observed on serial neuropsychologic testing in patients from both groups. Imaging studies were normal early and most commonly revealed neostriatal atrophy later in the course of the disease. In this report, we describe the characteristics of 12 patients with childhood-onset Huntington disease and review those previously reported, expanding our knowledge about the features of childhood-onset Huntington disease, underlining the differences with patients with adult-onset Huntington disease, and suggesting a differential phenotype within patients with childhood-onset Huntington disease depending on the age at onset.

Adolescent↗
PubMed2005

Silencing primary dystonia: lentiviral-mediated RNA interference therapy for DYT1 dystonia.

DYT1 is the most common inherited dystonia. Currently, there are no preventive or curative therapies for this dominantly inherited disease. DYT1 dystonia is caused by a common three-nucleotide deletion in the TOR1A gene that eliminates a glutamic acid residue from the protein torsinA. Recent studies suggest that torsinA carrying the disease-linked mutation, torsinA(DeltaE) acts through a dominant-negative effect by recruiting wild-type torsinA [torsinA(wt)] into oligomeric structures in the nuclear envelope. Therefore, suppressing torsinA(DeltaE) expression through RNA interference (RNAi) could restore the normal function of torsinA(wt), representing a potentially effective therapy regardless of the biological role of torsinA. Here, we have generated short hairpin RNAs (shRNAs) that mediate allele-specific suppression of torsinA(DeltaE) and rescue cells from its dominant-negative effect, restoring the normal distribution of torsinA(wt). In addition, delivery of this shRNA by a recombinant feline immunodeficiency virus effectively silenced torsinA(DeltaE) in a neural model of the disease. We further establish the feasibility of this viral-mediated RNAi approach by demonstrating significant suppression of endogenous torsinA in mammalian neurons. Finally, this silencing of torsinA is achieved without triggering an interferon response. These results support the potential use of viral-mediated RNAi as a therapy for DYT1 dystonia and establish the basis for preclinical testing in animal models of the disease.

Animals↗
PubMed2005

RNA interference in neuroscience: progress and challenges.

1.RNA interference (RNAi) is a recently discovered biological pathway that mediates post-transcriptional gene silencing. The process of RNAi is orchestrated by an increasingly well-understood cellular machinery. 2. The common entry point for both natural and engineered RNAi are double stranded RNA molecules known as short interfering RNAs (siRNAs), that mediate the sequence-specific identification and degradation of the targeted messenger RNA (mRNA). The study and manipulation of these siRNAs has recently revolutionized biomedical research. 3. In this review, we first provide a brief overview of the process of RNAi, focusing on its potential role in brain function and involvement in neurological disease. We then describe the methods developed to manipulate RNAi in the laboratory and its applications to neuroscience. Finally, we focus on the potential therapeutic application of RNAi to neurological disease.

Animals↗
PubMed2004

Aberrant cellular behavior of mutant torsinA implicates nuclear envelope dysfunction in DYT1 dystonia.

Torsion dystonia-1 (DYT1) dystonia, the most common inherited form of dystonia, is caused by a three base pair deletion that eliminates a single amino acid from the disease protein, torsinA. TorsinA is an "AAA" protein thought to reside in the endoplasmic reticulum (ER), yet both its cellular function and the basis for neuronal dysfunction in DYT1 remain unknown. A clue to disease pathogenesis is the fact that mutant, but not wild-type, torsinA forms membranous inclusions in cell culture. To explore the pathobiology of DYT1 dystonia, we generated PC12 neural cell lines that inducibly express wild-type or mutant torsinA. Although in this model torsinA displays some properties consistent with ER localization, mutant torsinA also accumulates in the nuclear envelope (NE), a structure contiguous with cytoplasmic ER. Consistent with this, membranous inclusions formed by mutant torsinA are shown to derive not from the ER, as thought previously, but from the NE. We demonstrate further that torsinA forms different disulfide-linked complexes that may be linked functionally to subcellular localization in the NE versus cytoplasmic ER. Despite mutant TA accumulation in NE structures, nucleocytoplasmic transport of a reporter protein was unaffected. These findings, together with parallel studies failing to demonstrate perturbation of ER function, implicate the NE as a primary site of dysfunction in DYT1. DYT1 dystonia can be added to the growing list of inherited neurological disorders involving the NE.

Active Transport, Cell Nucleus↗
PubMed2003

Toward therapy for DYT1 dystonia: allele-specific silencing of mutant TorsinA.

A three-nucleotide (GAG) deletion in the TOR1A gene is the most common cause of inherited dystonia, DYT1. Because the mutant protein, TorsinA (TA), is thought to act in a dominant manner to cause disease, inhibiting expression from the mutant gene represents a potentially powerful therapeutic strategy. In an effort to develop therapy for this disease, we tested whether small interfering RNA (siRNA) could selectively silence expression of mutant TA. Exploiting the three-base pair difference between wild-type and mutant alleles, we designed siRNAs to silence expression of mutant, wild-type, or both forms of TA. In transfected cells, siRNA successfully suppressed wild-type or mutant TA in an allele-specific manner: for example, mutant-specific siRNA reduced the levels of mutant TA to less than 1% of controls with minimal effect on wild-type TA expression. In cells expressing both alleles, thus simulating the heterozygous state, siRNA-mediated suppression remained robust and allele specific. Our siRNA studies demonstrate allele-specific targeting of a dominant neurogenetic disease gene and suggest the broad therapeutic potential of siRNA for DYT1 dystonia and other dominantly inherited neurological diseases.

Alleles↗
PubMed2003

Moyamoya-induced paroxysmal dyskinesia.

Moyamoya disease (MMD) is an uncommon intracranial vasculopathy that typically presents with ischemic or hemorrhagic stroke. Persistent choreoathetosis has been identified as a rare early manifestation of MMD. We present 2 patients with paroxysmal dyskinesia as the initial symptom of MMD, one resembling paroxysmal kinesigenic dyskinesia (PKD) and the other paroxysmal non-kinesigenic dyskinesia (PNKD). We also review the cases of moyamoya-induced chorea reported previously, none of which resembled PKD or PNKD. We hypothesize that both hormonal and ischemic factors may be implicated in the pathogenesis of these abnormal involuntary movements. These cases suggest that MMD should be included in the differential diagnosis of PKD and PNKD.

Adolescent↗
PubMed2003

Prolonged cortical electrical depression and diffuse vasospasm without ischemia in a case of severe hemiplegic migraine during pregnancy.

The pathophysiology of the neurological deficits in hemiplegic migraine remains unclear. Both neurogenic and vascular etiologies have been proposed to explain this phenomenon. We present the case of a patient with hemiplegic migraine in whom there was no diffusion weighted magnetic resonance imaging evidence of cerebral ischemia, despite persistent left hemiplegia and diffuse vasospasm on cerebral angiography, there was no diffusion weighted magnetic resonance imaging evidence of cerebral ischemia. In addition, hypoperfusional changes were seen diffusely, more so on the less symptomatic hemisphere, whereas depression of cortical electrical activity was seen for several days on the right side. These findings support the notion that although both neurogenic and vascular changes occur in hemiplegic migraine, the former seems to be a more likely explanation for the neurological deficits.

Adult↗
PubMed2002

Idiopathic brachial neuritis.

Idiopathic brachial neuritis is a well defined clinical condition that most commonly affects young adults, seen usually by primary care physicians, neurologists or orthopaedic surgeons. Its onset is characterized by acute, aching shoulder pain lasting a few days to weeks, followed by progressive shoulder girdle and upper extremity weakness and atrophy, with a slow but progressive recovery of motor function over 6 to 18 months. Its early recognition can help avoid unnecessary and potentially harmful diagnostic and therapeutic interventions, and avoid delays in prescribing appropriate therapies that may be helpful only early in the course of the disease. We present a case of idiopathic brachial neuritis and discuss important aspects of the disease and difficulties in reaching the correct diagnosis.

Brachial Plexus Neuritis↗