RESUMO
BACKGROUND AND PURPOSE: OnabotulinumtoxinA was effective and well tolerated for prophylaxis of headache in patients with chronic migraine (CM) in two randomized, double-blind, placebo-controlled, phase 3 trials. To further assess the safety and tolerability of onabotulinumtoxinA in CM prophylaxis in adults, the pooled safety data from four double-blind, placebo-controlled trials were analyzed. METHODS: The pooled analysis included two phase 2 and two phase 3 double-blind, placebo-controlled trials. The safety population was 2436 patients, 1997 of whom received ≥1 dose of onabotulinumtoxinA. The studies shared similar dosing intervals (approximately 12 weeks) with doses between 75 and 260 U. Safety assessments included adverse events (AEs), physical examination and clinical laboratory tests. RESULTS: OnabotulinumtoxinA was safe and well tolerated, with a low discontinuation rate (3.4%) due to AEs. The majority of patients in this pooled analysis received doses between 150 and 200 U, with an average of 163 U per treatment cycle. Of the 1997 patients who received any onabotulinumtoxinA injections, 1455 patients (72.9%) reported at least one AE. Neck pain (12.6%) was the most common onabotulinumtoxinA-associated AE, followed by muscle weakness (8.0%), musculoskeletal stiffness (6.1%) and eyelid ptosis (4.6%). Serious AEs were infrequent, occurring in 5.4% of patients who received any onabotulinumtoxinA treatment and 3.0% of patients receiving placebo. AEs were consistent with the known tolerability profile of onabotulinumtoxinA. CONCLUSIONS: Multiple treatments with onabotulinumtoxinA at doses of 75-260 U administered every 12 weeks, and up to five treatment cycles, were well tolerated for the prophylaxis of headache in adults with CM.
Assuntos
Toxinas Botulínicas Tipo A/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Adolescente , Adulto , Idoso , Toxinas Botulínicas Tipo A/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
Early-onset torsion dystonia is a movement disorder, characterized by twisting muscle contractures, that begins in childhood. Symptoms are believed to result from altered neuronal communication in the basal ganglia. This study identifies the DYT1 gene on human chromosome 9q34 as being responsible for this dominant disease. Almost all cases of early-onset dystonia have a unique 3-bp deletion that appears to have arisen idependently in different ethnic populations. This deletion results in loss of one of a pair of glutamic-acid residues in a conserved region of a novel ATP-binding protein, termed torsinA. This protein has homologues in nematode, rat, mouse and humans, with some resemblance to the family of heat-shock proteins and Clp proteases.
Assuntos
Cromossomos Humanos Par 9 , Distonia Muscular Deformante/genética , Chaperonas Moleculares , Transportadores de Cassetes de Ligação de ATP/genética , Idade de Início , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteínas de Transporte/química , Mapeamento Cromossômico , Análise Mutacional de DNA , Triagem de Portadores Genéticos , Ligação Genética , Marcadores Genéticos , Humanos , Judeus/genética , Linfócitos , Camundongos , Dados de Sequência Molecular , Mutação Puntual , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Ratos , Proteínas Recombinantes/biossíntese , Alinhamento de Sequência , Deleção de Sequência , Homologia de Sequência de Aminoácidos , Transcrição GênicaRESUMO
OBJECTIVES: This is the second of a pair of studies designed to evaluate the efficacy and safety of onabotulinumtoxinA (BOTOX) for prophylaxis of headaches in adults with chronic migraine. METHODS: PREEMPT 2 was a phase 3 study, with a 24-week, double-blind, placebo-controlled phase, followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections of onabotulinumtoxinA (155U-195U; n = 347) or placebo (n = 358) every 12 weeks for two cycles. The primary efficacy endpoint was mean change in headache days per 28 days from baseline to weeks 21-24 post-treatment. RESULTS: OnabotulinumtoxinA was statistically significantly superior to placebo for the primary endpoint, frequency of headache days per 28 days relative to baseline (-9.0 onabotulinumtoxinA/-6.7 placebo, p < .001). OnabotulinumtoxinA was significantly favoured in all secondary endpoint comparisons. OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few patients (3.5% onabotulinumtoxinA/1.4% placebo) discontinued due to adverse events. CONCLUSIONS: The results of PREEMPT 2 demonstrate that onabotulinumtoxinA is effective for prophylaxis of headache in adults with chronic migraine. Repeated onabotulinumtoxinA treatments were safe and well tolerated.
Assuntos
Toxinas Botulínicas Tipo A/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Fármacos Neuromusculares/uso terapêutico , Adolescente , Adulto , Idoso , Doença Crônica , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: This is the first of a pair of studies designed to assess efficacy, safety and tolerability of onabotulinumtoxinA (BOTOX) as headache prophylaxis in adults with chronic migraine. METHODS: The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 (PREEMPT 1) is a phase 3 study, with a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxinA (155 U-195 U; n = 341) or placebo (n = 338) (two cycles). The primary endpoint was mean change from baseline in headache episode frequency at week 24. RESULTS: No significant between-group difference for onabotulinumtoxinA versus placebo was observed for the primary endpoint, headache episodes (-5.2 vs. -5.3; p = 0.344). Large within-group decreases from baseline were observed for all efficacy variables. Significant between-group differences for onabotulinumtoxinA were observed for the secondary endpoints, headache days (p = .006) and migraine days (p = 0.002). OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few subjects discontinued due to adverse events. CONCLUSIONS: There was no between-group difference for the primary endpoint, headache episodes. However, significant reductions from baseline were observed for onabotulinumtoxinA for headache and migraine days, cumulative hours of headache on headache days and frequency of moderate/severe headache days, which in turn reduced the burden of illness in adults with disabling chronic migraine.
Assuntos
Toxinas Botulínicas Tipo A/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Fármacos Neuromusculares/uso terapêutico , Adolescente , Adulto , Idoso , Doença Crônica , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
Torsion dystonia is a movement disorder of unknown etiology characterized by loss of control of voluntary movements appearing as sustained muscle contractions and/or abnormal postures. Dystonic movements can be caused by lesions in the basal ganglia, drugs, or gene defects. Several hereditary forms have been described, most of which have autosomal dominant transmission with variable expressivity. In the Ashkenazi Jewish population the defective gene frequency is about 1/10,000. Here, linkage analysis using polymorphic DNA and protein markers has been used to locate a gene responsible for susceptibility to dystonia in a large, non-Jewish kinship. Affected members of this family have a clinical syndrome similar to that found in the Jewish population. This dystonia gene (ITD1) shows tight linkage with the gene encoding gelsolin, an actin binding protein, and appears by multipoint linkage analysis to lie in the q32-q34 region of chromosome 9 between ABO and D9S26, a region that also contains the locus for dopamine-beta-hydroxylase.
Assuntos
Cromossomos Humanos Par 9 , Distonia Muscular Deformante/genética , Polimorfismo de Fragmento de Restrição , Proteínas de Ligação ao Cálcio/genética , Mapeamento Cromossômico , Sondas de DNA , Dopamina beta-Hidroxilase/genética , Gelsolina , Ligação Genética , Marcadores Genéticos , Humanos , Proteínas dos Microfilamentos/genética , LinhagemRESUMO
BACKGROUND: Continuous infusion of intrathecal (IT) baclofen is a highly effective standard therapy for severe spasticity of spinal origin. By contrast, there is limited clinical experience regarding the use of IT baclofen in treating patients with dystonia, and little is known regarding the indications for treatment, efficacy, and safety of IT baclofen in this disorder. OBJECTIVE: To study retrospectively the effects of IT baclofen in treating 25 patients with severe segmental or generalized dystonia. SETTING: Neurological Institute, Columbia-Presbyterian Medical Center, New York, NY. PATIENTS: Twenty-five patients with severe segmental or generalized dystonia that was refractory to oral medications underwent IT baclofen test dosing. In addition to dystonia, 17 patients had spasticity or painful spasms. Thirteen of 25 patients responded to the test doses of IT baclofen, according to unblinded neurological assessments that included the patient's subjective report; all 13 underwent implantation of a pump for continuous IT baclofen infusion. RESULTS: In contrast to reports of patients with spasticity of spinal origin, those with dystonia in the present series had a lower response rate to bolus IT baclofen doses and a smaller degree of clinical improvement. For 10 of the 13 responders to the test doses of IT baclofen, dystonia rating scale scores of videotaped examinations by blinded observers detected no significant change (P < .07) in severity of dystonia. Retrospective data from 11 of 13 patients with implantable pumps, followed up for a mean interval of 21 months after pump insertion, showed continuing efficacy in 6 individuals (55%), based on a determination of patient satisfaction; however, only 3 patients (27%) reported a sustained improvement in functional capacity. Five (38%) of the 13 patients with implantable pumps experienced severe complications that required hospitalization. CONCLUSIONS: Despite recent reports that have described the benefit in small numbers of patients with dystonia, we concluded that the role of IT baclofen in treating severe dystonia remains uncertain. Intrathecal baclofen may be more effective when dystonia is associated with spasticity or pain. In the present series, we detected no significant difference in the response to IT baclofen in patients with or without spasticity or pain, perhaps owing to the small sample size.
Assuntos
Baclofeno/administração & dosagem , Distonia/tratamento farmacológico , Humanos , Bombas de Infusão Implantáveis , Estudos Retrospectivos , Medula EspinalRESUMO
Levodopa therapy remains the major form of treatment for the symptoms of Parkinson's disease (PD). However, there has been a suspicion that its use may hasten the progression of nigral cell degeneration. This concept is based on the ability of levodopa to generate reactive oxygen species and the apparent involvement of oxidative stress as a component of the degenerative process that occurs in PD. Indeed, in vitro autoxidation of levodopa causes oxidative stress, leading to neuronal destruction by necrosis or apoptosis. However, its chronic administration to normal rats or primates has not been associated with clear evidence for destruction of the nigrostriatal pathway. In contrast, in situations in which the nigrostriatal tract is already damaged, there is some evidence to suggest that levodopa treatment can produce further cell destruction associated with oxidative processes. However, levodopa does not appear to be toxic to the development of fetal nigral neurons or to the survival of fetal cell transplants. There is no clinical evidence to suggest that levodopa has adverse effects on dopamine cells in normal humans or on the viability of remaining dopaminergic cells in patients with PD. However, it is only now that specific clinical trials designed to examine the potential neurotoxicity of levodopa are being undertaken.
Assuntos
Antiparkinsonianos/toxicidade , Levodopa/toxicidade , Doença de Parkinson/tratamento farmacológico , Animais , Antiparkinsonianos/farmacocinética , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dopamina/metabolismo , Humanos , Levodopa/farmacocinética , Degeneração Neural/induzido quimicamente , Neurônios/efeitos dos fármacos , Doença de Parkinson/etiologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Substância Negra/efeitos dos fármacosRESUMO
Botulinum toxin is the most neurotoxic substance known, with a specific action at cholinergic synapses. Acting as a zinc endopeptidase, botulinum toxin cleaves specific proteins involved in vesicle fusion, thereby preventing release of acetylcholine. The therapeutic effect of the toxin taken up presynaptically at the neuromuscular junction is to weaken muscle. Botulinum toxin type A (BTX-A) has been shown to be safe and effective in the treatment of cervical dystonia (CD; also known as spasmodic torticollis). In patients with CD, injections of botulinum toxin dampen or eliminate involuntary muscle activity and improve control of neck movement, pain, and range of motion. To successfully use botulinum toxin as a therapeutic modality, targeting the dystonic muscles, injecting a sufficient quantity of toxin and minimizing diffusion into uninvolved muscle collectively provide the best outcome with the fewest adverse reactions. EMG guidance may allow more precise injections. To maintain responsiveness to the toxin over repeated injections, using the lowest dose at the longest dosing interval has been suggested.
Assuntos
Distonia/tratamento farmacológico , Músculos do Pescoço , HumanosRESUMO
Stuttering is an action-induced speech disorder with involuntary, audible, or silent repetitions or prolongations in the utterance of short speech elements (sounds, syllables) and words. Symptomatic treatment programs frequently have initial success; persistent benefit is variable and many patients remain disabled. Stuttering has many characteristics similar to spasmodic dysphonia (laryngeal dystonia), often including the presence of adductor laryngeal spasms that obstruct airflow (glottal block). We hypothesized that relief of the spasmodic dysphonic glottal blocks in stutterers would modify the stuttering phenomenon and increase fluency. We therefore studied the effects of bilateral vocal fold injections of botulinum toxin type A (BTX) on dysfluency and speech characteristics in stuttering. We treated 14 adult patients (12 men, 2 women) with persistent stuttering and glottal block who previously failed standard speech therapy with 1.25 U BTX into each thyroarytenoid (vocalis) muscle. Fluency evaluations included the Stuttering Severity Instrument, the Perceptions of Stuttering Inventory, and a global rating scale (percent of normal function). Patients were evaluated at baseline and at 2-, 6-, and 12-week follow-up visits. Improvement in fluency documented by each rating instrument occurred at 2 and 6 weeks, with functional relapse by 12 weeks in most patients. We conclude that therapeutic laryngeal injections of botulinum toxin are useful in the management of stuttering with glottal block and result in a moderate improvement in fluency. When an adult patient with developmental stuttering with glottal blocks has failed speech interventional therapy and presents for treatment, a trial of BTX can be considered early.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Toxinas Botulínicas/uso terapêutico , Laringe , Gagueira/tratamento farmacológico , Adulto , Idade de Início , Toxinas Botulínicas/administração & dosagem , Toxinas Botulínicas/efeitos adversos , Eletromiografia , Feminino , Seguimentos , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Autoavaliação (Psicologia) , Gagueira/fisiopatologia , Fatores de TempoRESUMO
Patients with advanced Parkinson's disease (PD) frequently suffer disabling motor complications that cannot be satisfactorily controlled with medical therapy. Deep brain stimulation (DBS) has recently been introduced by Benabid and his colleagues in Grenoble, France, as a new surgical procedure for the treatment of PD patients. DBS simulates the effects of a lesion without the need to make a destructive brain lesion. In this procedure, an electrode is implanted in the brain target and connected to a subcutaneous pacemaker. DBS of the ventro-intermediate (Vim) nucleus of the thalamus has been shown to ameliorate tremor in patients with tremor-dominant PD. DBS of the subthalamic nucleus (STN) and globus pallidus pars interna (GPi) have been shown to improve all of the cardinal features of PD and to markedly reduce dyskinesia and motor fluctuations. Adverse events are associated with the surgical procedure, the device, and stimulation, but the procedure is usually well tolerated. On the basis of these findings, the FDA has recently approved unilateral DBS of the Vim for treatment of tremor in PD and is currently considering approval of DBS for STN and GPi. This article reviews existing information with respect to DBS.
Assuntos
Encéfalo/cirurgia , Terapia por Estimulação Elétrica , Doença de Parkinson/cirurgia , Doença de Parkinson/terapia , HumanosRESUMO
A mutation of the DYT1 gene, which codes for torsinA, has been identified as the cause of one form of autosomal dominantly inherited dystonia. TorsinA immunohistochemistry was used to examine a case of DYT1, and several cases of non-DYT1, dystonia. No evidence was found for alterations of immunoreactivity at the light microscopic level, specifically neither cytoplasmic aggregations nor colocalization of torsinA immunoreactivity with a marker for endoplasmic reticulum. These findings contrast with results of recent cell culture studies of torsinA.
Assuntos
Encéfalo/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Distúrbios Distônicos/genética , Distúrbios Distônicos/metabolismo , Chaperonas Moleculares , Mutação , Adulto , Encéfalo/patologia , Citoplasma/metabolismo , Distúrbios Distônicos/patologia , Retículo Endoplasmático/metabolismo , Humanos , Imuno-Histoquímica , MasculinoRESUMO
We report 10 patients with delayed-onset dystonia associated with perinatal asphyxia and 2 associated with asphyxia in childhood. In the perinatal group, the mean age of onset was 12.9 years. Among these patients, dystonia continued to progress for a mean of 7 years, and as long as 28 years. These patients had moderate motor disability; none was wheelchair-bound, and thus their prognosis was better than that of the childhood-onset idiopathic torsion dystonias. The most frequently beneficial drugs were anticholinergics. Since some of these patients closely resembled cases of idiopathic torsion dystonia, the prior occurrence of asphyxia should be used as a criterion of exclusion for that diagnosis.
Assuntos
Envelhecimento/fisiologia , Asfixia Neonatal/complicações , Distonia/etiologia , Asfixia Neonatal/diagnóstico , Asfixia Neonatal/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Desenvolvimento Infantil , Pré-Escolar , Distonia/tratamento farmacológico , Distonia/fisiopatologia , Eletroencefalografia , Feminino , Humanos , Hipóxia/complicações , Lactente , Recém-Nascido , Masculino , Parassimpatolíticos/uso terapêutico , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
A 72-year-old man had severe malabsorption, progressive retinopathy, and spinocerebellar degeneration 32 years after gastric surgery, blind loop formation, and intestinal bacterial overgrowth. Clinical and pathologic features were typical of vitamin E deficiency; vitamin E was nearly undetectable in serum and profoundly low in adipose tissue. Vitamin E blood levels initially improved on treatment with antibiotics; after additional vitamin E supplementation, there was clinical improvement.
Assuntos
Síndrome da Alça Cega/complicações , Doenças Cerebelares/complicações , Doenças da Medula Espinal/complicações , Deficiência de Vitamina E/complicações , Absorção , Idoso , Humanos , Masculino , Músculos/inervação , Músculos/patologia , Degeneração Neural , Sistema Nervoso/patologia , Condução Nervosa , Complicações Pós-Operatórias , Úlcera Gástrica/cirurgia , Deficiência de Vitamina E/patologia , Deficiência de Vitamina E/fisiopatologiaRESUMO
We performed electrophysiologic testing in 10 patients with abetalipoproteinemia (ABL). Peripheral nerve studies implied an axonal disorder. Visual evoked potentials demonstrated prolonged P100 latency in three patients and abnormal electroretinograms in six. Somatosensory evoked potentials indicated dorsal column dysfunction in eight patients. Brainstem auditory evoked potentials were normal. Findings were consistent with the known neuropathology of ABL and of experimental vitamin E deficiency. Stabilization or improvement in electrophysiologic findings occurred with vitamin E supplementation. Neurophysiologic tests document retinal, central somatosensory and peripheral nerve lesions in vitamin E deficiency and provide an objective indication of response to treatment.
Assuntos
Abetalipoproteinemia/fisiopatologia , Nervos Periféricos/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Deficiência de Vitamina E/fisiopatologia , Adolescente , Adulto , Idoso , Tronco Encefálico/fisiopatologia , Pré-Escolar , Eletrofisiologia , Eletrorretinografia , Potenciais Evocados Auditivos , Potenciais Somatossensoriais Evocados , Potenciais Evocados Visuais , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Condução Nervosa , Doenças do Sistema Nervoso Periférico/etiologia , Doenças Retinianas/fisiopatologia , Deficiência de Vitamina E/complicaçõesRESUMO
BACKGROUND: The term chorea-acanthocytosis describes a heterogeneous group of neurodegenerative disorders with variable clinical features and modes of inheritance. The characteristic acanthocytic appearance of red blood cells is attributed to abnormalities of a membrane protein, band 3, although the relationship between this and the neurodegenerative process has yet to be determined. OBJECTIVE: To describe features of phenotype, inheritance, and neuropathological findings in a family with this disorder. METHODS: Clinical and hematologic evaluations were performed on all available family members and neuropathological examination was performed on one case. RESULTS: Autosomal dominant inheritance was evident, with variable clinical features of chorea or parkinsonism, marked cognitive changes, but no seizures or peripheral neurologic abnormalities. Abnormalities of band 3 were demonstrated on gel electrophoresis of red blood cell membranes. Neuropathological examination revealed severe neuronal loss of the caudate-putamen and intranuclear inclusion bodies in many areas of the cerebral cortex. These inclusion bodies were immunoreactive for ubiquitin, expanded polyglutamine repeats, and torsinA. CONCLUSIONS: This family extends the genetic spectrum of chorea-acanthocytosis to include autosomal dominant inheritance, possibly due to expanded trinucleotide repeats. Intraneuronal inclusion bodies have recently been associated with a wide range of inherited neurodegenerative disorders and may provide a clue to etiopathogenesis, in addition to potentially indicating a function of torsinA.
Assuntos
Coreia/genética , Coreia/patologia , Corpos de Inclusão/química , Corpos de Inclusão/patologia , Neurônios/patologia , Peptídeos/análise , Acantócitos/patologia , Adulto , Atrofia , Córtex Cerebral/química , Córtex Cerebral/patologia , Feminino , Humanos , Corpos de Inclusão/genética , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neurônios/química , LinhagemRESUMO
Type F botulinum toxin can be used for treating patients with dystonia who become refractory to type A toxin injection due to antibody development. We compared the therapeutic efficacy of type F botulinum toxin to that of type A toxin in a self-controlled, double-blind clinical trial. In nine patients with blepharospasm, we injected type A toxin on one side and the same units of type F toxin on the other side. Although the onset of clinical effect, maximal benefit, and adverse reactions were similar between type A and F toxins, the duration of the clinical effect was significantly shorter on the side injected with type F toxin. Although type F toxin proved its promise as an alternative to type A toxin, its usefulness is limited by the shorter duration of action.
Assuntos
Blefarospasmo/tratamento farmacológico , Toxinas Botulínicas/uso terapêutico , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Some patients with an 18p- syndrome show dystonia, and a focal dystonia gene has been mapped to chromosome 18p. The authors evaluated the extent of the deletion in three patients with an 18p- syndrome and dystonia using 14 DNA markers on 18p. A common deleted area, covering the DYT7 locus, places the putative dystonia gene between the telomere of 18p and D18S1104 (49.6 cM). Dystonia in these patients may be caused by haploinsufficiency of the DYT7 gene, a new dystonia gene on 18p, or may result from developmental brain anomalies.
Assuntos
Cromossomos Humanos Par 18/genética , Distonia/genética , Adulto , Deleção Cromossômica , Mapeamento Cromossômico , DNA/análise , Feminino , Humanos , Cariotipagem , Masculino , SíndromeRESUMO
A gene (DYT1) for idiopathic torsion dystonia (ITD) was mapped to chromosome 9q34 in non-Jewish and Jewish families; the dystonia in these families usually began in childhood, with the limb muscles affected first. The role of the DYT1 gene in adult-onset and cervical- or cranial-onset ITD is unknown. We examined 53 individuals from four generations of a non-Jewish North American family with adult-onset ITD. There were seven affected family members, with a mean age at onset of 28.4 years (range, 7 to 50 years). In six of the seven, the neck was affected first. All seven developed cervical dystonia, and dysarthria or dysphonia occurred in five. Linkage data excluded the region containing the DYT1 locus, indicating that DYT1 was not responsible for ITD in this family. This study provides evidence that a gene other than DYT1 is responsible for some cases of adult cervical-onset dystonia.
Assuntos
Cromossomos Humanos Par 9 , Distonia Muscular Deformante/genética , Adolescente , Adulto , Idade de Início , Criança , Cristianismo , Mapeamento Cromossômico , Distonia Muscular Deformante/diagnóstico , Distonia Muscular Deformante/fisiopatologia , Família , Feminino , Triagem de Portadores Genéticos , Ligação Genética , Marcadores Genéticos , Alemanha/etnologia , Humanos , Judeus/genética , Escore Lod , Masculino , Pessoa de Meia-Idade , América do Norte , LinhagemRESUMO
Early-onset (< 28 years) primary dystonia in most Ashkenazi Jews is due to a single founder mutation in the DYT1 gene on chromosome 9q34, as determined by very strong linkage disequilibrium with a haplotype of 9q34 alleles at surrounding marker loci. The role of this mutation in individuals with secondary causes for dystonia has never been tested, although environmental insults, such as neuroleptic exposure or perinatal asphyxia, are proposed to precipitate dystonia in genetically predisposed individuals. We assessed 9q34 haplotypes in 40 Ashkenazi patients with secondary dystonia; 25 had early onset of symptoms, including 15 with exposure to neuroleptic medication or perinatal asphyxia. Of the 25 patients with early onset, 9 were considered phenocopies of DYT1 having normal examinations except for dystonia, normal radiographic and other laboratory studies, and onset in a limb or the neck. Only one individual whose dystonia developed in the setting of a measles infection carried the associated haplotype. Our findings indicate that clinical diagnostic criteria that include historical information to detect tardive dystonia and perinatal asphyxia discriminate primary dystonia due to the DYT1 founder mutation. We found no evidence that the DYT1 founder mutation contributes to secondary dystonia.
Assuntos
Cromossomos Humanos Par 9 , Distonia/etiologia , Distonia/genética , Adolescente , Adulto , Idade de Início , Idoso , Alelos , Criança , Feminino , Ligação Genética , Marcadores Genéticos , Haplótipos , Humanos , Judeus/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , FenótipoRESUMO
OBJECTIVE: To develop diagnostic testing guidelines for the DYT1 GAG deletion in the Ashkenazi Jewish (AJ) and non-Jewish (NJ) primary torsion dystonia (PTD) populations and to determine the range of dystonic features in affected DYT1 deletion carriers. METHODS: The authors screened 267 individuals with PTD; 170 were clinically ascertained for diagnosis and treatment, 87 were affected family members ascertained for genetic studies, and 10 were clinically and genetically ascertained and included in both groups. We used published primers and PCR amplification across the critical DYT1 region to determine GAG deletion status. Features of dystonia in clinically ascertained (affected) DYT1 GAG deletion carriers and noncarriers were compared to determine a classification scheme that optimized prediction of carriers. The authors assessed the range of clinical features in the genetically ascertained (affected) DYT1 deletion carriers and tested for differences between AJ and NJ patients. RESULTS: The optimal algorithm for classification of clinically ascertained carriers was disease onset before age 24 years in a limb (misclassification, 16.5%; sensitivity, 95%; specificity, 80%). Although application of this classification scheme provided good separation in the AJ group (sensitivity, 96%; specificity, 88%), as well as in the group overall, it was less specific in discriminating NJ carriers from noncarriers (sensitivity, 94%; specificity, 69%). Using age 26 years as the cut-off and any site at onset gave a sensitivity of 100%, but specificity decreased to 54% (63% in AJ and 43% in NJ). Among genetically ascertained carriers, onset up to age 44 years occurred, although the great majority displayed early limb onset. There were no significant differences between AJ and NJ genetically ascertained carriers, except that a higher proportion of NJ carriers had onset in a leg, rather than an arm, and widespread disease. CONCLUSIONS: Diagnostic DYT1 testing in conjunction with genetic counseling is recommended for patients with PTD with onset before age 26 years, as this single criterion detected 100% of clinically ascertained carriers, with specificities of 43% to 63%. Testing patients with onset after age 26 years also may be warranted in those having an affected relative with early onset, as the only carriers we observed with onset at age 26 or later were genetically ascertained relatives of individuals whose symptoms started before age 26 years.