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Biomedical subjects

S Bressman

Publications and source records attributed to S Bressman.

At least 19 recordsLinked to original sources
PubMed2006

Genetics of dystonia.

Primary torsion dystonia (PTD) has a broad clinical spectrum, with earlier onset of symptoms associated with more generalized muscle involvement. The causes for most dystonia are unknown although several monogenic subtypes have been identified. One important genetic cause of PTD is DYT1; a three base pair deletion in this gene is a major cause for early-onset dystonia. Its identification has allowed the development of cellular and animal models; it has also permitted studies that identify both "manifesting" and "non-manifesting" DYT1 mutation carriers. These studies have expanded our understanding of clinical expression to include psychiatric symptoms and also have enabled imaging studies of endophenotypes. These advances provide a widened platform for future research.

Age of Onset↗
PubMed2004

Regional metabolism in primary torsion dystonia: effects of penetrance and genotype.

BACKGROUND: The authors have previously used [18F]fluorodeoxyglucose (FDG) PET to identify a reproducible pattern of regional glucose metabolism that was expressed in both manifesting and nonmanifesting carriers of the DYT1 primary dystonia mutation. OBJECTIVE: To identify specific regions that discriminated subjects according to clinical penetrance and genotype. METHODS: FDG PET was used to scan 12 nonmanifesting and 11 manifesting DYT1 gene carriers, 6 nonmanifesting DYT6 gene carriers and 7 manifesting DYT6 gene carriers, as well as 11 control subjects. The data from all five groups were analyzed with statistical parametric mapping and analysis of variance with posthoc contrasts. RESULTS: A dissociation of metabolic changes was found related to phenotype and genotype. Manifesting gene carriers of both genotypes exhibited bilateral hypermetabolism in the presupplementary motor area (Brodmann area [BA] 6) and parietal association cortices (BA 40/7) compared with the respective nonmanifesting counterparts. By contrast, genotype-specific increases in metabolism were found in the putamen, anterior cingulate (BA 24/32), and cerebellar hemispheres of DYT1 carriers. Genotype-specific changes in DYT6 involved hypometabolism of the putamen and hypermetabolism in the temporal cortex (BA 21). CONCLUSIONS: Dystonia may be associated with abnormal movement preparation caused by defective sensorimotor integration. Whereas clinical manifestations are related to cortical dysfunction, metabolic abnormalities in subcortical structures may represent trait features that are specific for individual dystonia genotypes.

Adolescent↗
PubMed2001

COMT-dependent protection of dopaminergic neurons by methionine, dimethionine and S-adenosylmethionine (SAM) against L-dopa toxicity in vitro.

L-dopa may be toxic to dopamine neurons, possibly due to catechol-autoxidation. Catechols are O-methylated by catechol-O-methyltransferase (COMT) in a SAM consuming reaction, preventing the initiation of catechol autoxidation. We hypothesized that SAM or SAM-precursors ameliorate L-dopa neurotoxicity, in a COMT-dependent fashion. We tested this hypothesis in primary mesencephalic cultures by adding 200 microM L-dopa with 2 mM methionine or 1 mM dimethionine or 0.5 mM SAM with or without 0.2 microM of the COMT-inhibitor 2', 5'-dinitrocatechol (OR 486). L-dopa was found to be neurotoxic as the surviving neurons had fewer and shorter processes. Methionine, dimethionine and SAM all protected DA neurons against damaged induced by L-dopa. The COMT inhibitor dinitrocatechol (DNC) completely abolished the protective effect against L-dopa toxicity. We conclude that supplementation with methionine, dimethionine or SAM ameliorates L-dopa neurotoxicity to dopamine neurons, while inhibition of COMT may aggravate or unmask L-dopa neurotoxicity.

Animals↗
PubMed2000

Evaluation of the role of the D2 dopamine receptor in myoclonus dystonia.

A novel Val154-->Ile mutation in the D2 dopamine receptor (DRD2) on chromosome 11q23 has recently been shown to be associated with myoclonus dystonia (M-D) in one large family. Sequence analysis of the DRD2 gene in 5 M-D patients from different families did not reveal any mutations, nor was there evidence of linkage to the 11q23 region in the DRD2 gene in four other families. Receptor binding and signal transduction assays of the DRD2 mutant and wild-type receptors revealed identical agonist and antagonist affinities and functional responses. These studies suggest that M-D is genetically heterogeneous. The molecular mechanisms through which the Val-->Ile mutation may contribute to M-D remain to be determined.

Adolescent↗
PubMed2000

A novel mitochondrial 12SrRNA point mutation in parkinsonism, deafness, and neuropathy.

The objective of this study was to determine whether a mitochondrial DNA mutation and defective oxidative phosphorylation are present in a pedigree with maternally inherited sensorineural deafness, levodopa-responsive parkinsonism, and neuropathy. We sequenced the mitochondrial-encoded ribosomal RNA, cytochrome c oxidase, and transfer RNA genes by cycle sequencing. A polymerase chain reaction-based restriction enzyme assay with mismatched primers was employed to show heteroplasmy of a novel 12SrRNA mutation in the proband and to screen control subjects. Spectrophotometric mitochondrial respiratory chain assays were performed in transformed lymphoblasts from the proband and 12 normal controls. A novel, heteroplasmic, maternally inherited 12SrRNA point mutation (T1095C) was found in the pedigree. Respiratory chain enzyme analysis in cultured lymphocytes from the proband revealed a significant reduction in cytochrome c oxidase activity. Secondary structure predicts that this mutation disrupts a highly conserved loop in the small subunit ribosomal RNA, which is important in the initiation of mitochondrial protein synthesis. The mutation was not found in 270 controls of diverse ethnic origins. We conclude that this mutation is pathogenic and causes an oxidative phosphorylation defect by interfering with mitochondrial protein synthesis.

DNA, Mitochondrial↗
PubMed1999

Association of a missense change in the D2 dopamine receptor with myoclonus dystonia.

Hereditary autosomal dominant myoclonus dystonia (MD) is a movement disorder characterized by involuntary lightning jerks and dystonic movements and postures alleviated by alcohol. Although various large families with MD have been described, no positive linkage has been found to a chromosomal location. We report a family with eight members with MD. Linkage analysis identified a 23-centimorgan region on chromosome 11q23 that cosegregates with the disease state (maximum multipoint logarithm of odds score = 2.96 at D11S897). This region contains an excellent candidate gene for involvement in the etiology of MD, the D2 dopamine receptor (DRD2) gene. Neurotransmission mediated by DRD2 is known to have a key role in the control of movement and also has been implicated in reward and reinforcement mechanisms and psychiatric disorders. Sequencing of the coding region of DRD2 indicated that all affected and obligate carriers were heterozygous for a Val154Ile change in exon 3 of the protein, which is highly conserved across species. This change was found neither in other unaffected members of the pedigree nor in 250 control chromosomes. Our finding provides evidence for the involvement of DRD2 in a disorder of the central nervous system and should lead to further insight into the function of the dopaminergic system in dystonia and other movement and mood disorders.

Adolescent↗
PubMed1999

The effect of estrogen replacement on early Parkinson's disease.

OBJECTIVE: To determine the effect of estrogen in postmenopausal women with early PD. BACKGROUND: The role of estrogen in PD is highly disputed, with some studies suggesting a prodopaminergic effect and others suggesting an antidopaminergic effect. Owing to controversy and the small sample sizes of prior studies, further investigation is warranted. METHODS: A retrospective chart review was carried out from a computerized database of patients at Columbia-Presbyterian, including only women who had symptoms of presumed PD for less than 5 years and who had not yet been on L-dopa at their first visit. Multiple regression was performed to assess the effects of estrogen on disease, measured by total Unified Parkinson's Disease Rating Scale (UPDRS) score, as a function of symptom duration, age at onset, education, smoking, dopamine agonist, and deprenyl use. RESULTS: Of the women who were not on L-dopa and had PD for less than 5 years at their first visit, 34 were found to have received estrogen at some time and 104 had never received estrogen. Excluding the women who had taken dopamine agonists, analysis yielded a multiple regression coefficient of 0.52 (p < 0.001). Estrogen use was negatively correlated with UPDRS score; age at onset and symptom duration were positively correlated (p < 0.05). CONCLUSIONS: We found a positive association between estrogen use and lower symptom severity in women with early PD not yet taking L-dopa. These results indicate that estrogen therapy should not be avoided and may be beneficial in early PD, at least prior to the initiation of L-dopa.

Age of Onset↗
PubMed1999

Genetic testing for early-onset torsion dystonia (DYT1): introduction of a simple screening method, experiences from testing of a large patient cohort, and ethical aspects.

Early-onset, generalized primary torsion dystonia (PTD) is an autosomal dominantly inherited disorder, characterized by involuntary movements and abnormal postures. The majority of cases are caused by a 3-bp deletion in the DYT1 gene on chromosome 9q34 that allows for specific genetic testing. We developed a simple, reliable, and cost-effective, PCR-based screening method for this mutation. Testing results from a cohort of 550 cases, including patients with different forms of dystonia and unclassified movement disorders, revealed that 72.2% of the patients with typical early-onset generalized PTD carried the GAG deletion in the DYT1 gene. Among 300 cases with late-onset focal/segmental dystonia, only 3 patients tested positive for the GAG deletion whereas 12.8% of the patients with an unclassified movement disorder were GAG positive. Our results confirm a genotype/phenotype correlation in early-onset PTD and show that application of strict clinical criteria leads to accurate prediction of carrier status in more than two-thirds of patients with this type of dystonia. Currently, we suggest that testing be recommended in individuals with age of onset of dystonia below 30 years and/or a positive family history of early-onset PTD. Testing is not recommended in patients with onset of symptoms after 30 years or in asymptomatic individuals under the age of 18.

Adult↗
PubMed1999

Pediatric movement disorders.

Movement disorders in children encompass disorders of motor control--both hyperkinetic (excessive movement) and hypokinetic (decreased movement). This article focuses on the hyperkinetic movement disorders, particularly tremor, Wilson's disease, dystonia, tics and Tourette syndrome, chorea, myoclonus, neuroleptic-induced movement disorders, and psychogenic movement disorders. Phenomenology of the disorders as well as clinical presentation, basic pathophysiology, genetics, and treatment are discussed.

Antipsychotic Agents↗
PubMed1998

Exteroceptive and interoceptive stimuli in dystonia.

Some patients with torsion dystonia experience a dramatic increase or decrease in symptoms when performing specific activities. The activities that influence dystonic symptoms vary from person to person. An activity or sensory stimulus that reduces symptoms has been called a "sensory trick" or, in cervical dystonia, a "geste antagoniste." When a single activity induces symptoms of dystonia, the dystonia is called "task specific." We have discovered that in some patients, thinking about a sensory trick or task affects the dystonia in the same way as actually performing the activity. We present three representative patients, and discuss the relevance of this observation to the understanding of dystonia.

Awareness↗
PubMed1997

Ethnic variation in the clinical expression of idiopathic torsion dystonia.

Although childhood, limb-onset idiopathic torsion dystonia (ITD) is at increased prevalence among Jews, and Ashkenazi Jews with this form of ITD show linkage disequilibrium for a unique haplotype, little else is known about phenotypic or genetic variation in ITD among ethnic groups. We assessed clinical features in 786 ITD patients and determined the relative frequencies of various clinical forms of ITD in the major ethnic groups. Several differences in age-at-onset and site-at-onset distributions among groups were demonstrated. As expected, Ashkenazi Jews had an earlier age-at-onset distribution than did non-Jewish Caucasians. In the early-onset group, Jews were less likely to have cervical onset and more likely to have onset in the limbs than were non-Jewish Caucasians (p < 0.01). Among late-onset cases, Jews had less cervical onset and more cranial onset than did non-Jewish Caucasians (p < 0.01). African-Americans showed suggestive differences in both age at onset and site at onset as compared with the two caucasian groups, with an intermediate age at onset, a deficit of leg onset, and an excess of cranial and larynx onset. Subgroups of non-Jewish Caucasians showed no significant differences from each other. The observed ethnic variations in age at onset and site at onset of ITD suggest population differences in disease-causing alleles or loci. However, environmental influences on expression of ITD can not be excluded.

Adolescent↗
PubMed1995

Dystonia in a patient with deletion of 18q.

This is the first reported case of dystonia with a partial deletion of the long arm (q) of chromosome 18. Neurologic findings in the 18q- syndrome include mental retardation, seizures, nystagmus, incoordination, tremor, and chorea. A 36-year-old woman with an 18q terminal deletion [karyotype 46,XX,del(18)(q22.2)] had hypothyroidism, diabetes mellitus, borderline intelligence, short stature, short neck, sensorineural hearing loss, and sensorimotor axonal neuropathy. Parents' karyotypes were normal. She had had incoordination and writing difficulty since childhood. Posturing and tremor of the head began at age 16, followed by arm tremors. She had jaw deviation and tremor, neck tremor with retrocollis, involuntary pronation of the right arm, coarse postural and severe action tremor, and tight pen grip with dystonic wrist extension on writing. The 18q- syndrome should be added to the list of genetic causes of secondary dystonia. A karyotype analysis should be considered in secondary dystonias, particularly when there are associated features such as short stature and endocrinopathies.

Adult↗
PubMed1995

Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population.

We have examined data on six closely linked microsatellite loci on chromosome 9q34 from 59 Ashkenazi Jewish families with idiopathic torsion dystonia (ITD). Our data show that the vast majority (> 90%) of early-onset ITD cases in the Ashkenazi population are due to a single founder mutation, which we estimate first appeared approximately 350 years ago. We also show that carriers preferentially originate from the northern part of the historic Jewish Pale of settlement (Lithuania and Byelorussia). The recent origin of this dominant mutation and its current high frequency (between 1/6,000 and 1/2,000) suggest that the Ashkenazi population descends from a limited group of founders, and emphasize the importance of genetic drift in determining disease allele frequencies in this population.

Alleles↗
PubMed1988

Clonazepam, haloperidol, and clonidine in tic disorders.

We reviewed the treatment outcomes of 81 patients with multifocal tic disorders followed in our movement disorders clinic. From the three drugs used, rank orders of effectiveness were haloperidol, clonazepam, and clonidine. Because of the risk of tardive dyskinesia, we suggest first a trial with clonazepam, later combined with clonidine if clonazepam alone is not effective. Haloperidol should be reserved for the most disabling cases, and given only after trials with both clonazepam and clonidine have failed.

Child↗
PubMed1986

Essential myoclonus.

The clinical characteristics of 15 patients with essential myoclonus are evaluated. The course of illness was one of initial worsening followed by a stable or improved state. Only two patients had positive family histories of involuntary movements. Nine patients had segmental distribution despite a careful search for etiology; in two of these patients, myoclonus was rhythmic. The trunk and proximal limbs were the most frequently affected body regions. Clonazepam improved myoclonus in 10 of 13 patients, two of whom had complete resolution of symptoms. On review of the salient features of the myoclonus, we discerned four phenomenological subcategories: (a) oscillatory myoclonus, (b) rhythmic segmental myoclonus, (c) nonrhythmic segmental myoclonus, and (d) nonrhythmic multifocal myoclonus.

Adolescent↗
PubMed1986

Biotin-responsive encephalopathy with myoclonus, ataxia, and seizures.

Prominent neurological abnormalities, including myoclonus, seizures, ataxia, and hearing loss, have been noted in juvenile-onset biotin-responsive MCD. The underlying defect in many of these patients, who generally present in the first year of life, appears to be a deficiency of biotinidase. We have presented a young woman with adult-onset myoclonus, ataxia, hearing loss, seizures, hemianopia, and hemiparesis who responded to pharmacologic dosages of biotin. Although she displayed many of the clinical and biochemical features of juvenile-onset MCD, she did not have a biotinidase deficiency, and the underlying defect remains to be determined. Because of her response to biotin, we have advocated that other patients with unexplained myoclonus syndromes be evaluated for biotin-dependent carboxylase deficiencies and undergo a therapeutic trial with biotin.

Adult↗
PubMed1985

Acetylcholinesterase activity in patients with torsion dystonia. Measurement in erythrocyte membranes.

Anticholinergic therapy provides symptomatic relief in many patients with dystonia. The mechanism underlying this therapeutic action is poorly understood; however, one possibility is that the degradation of acetylcholine is perturbed in these conditions. To investigate this possibility, acetylcholinesterase activity was measured in erythrocyte membranes from healthy volunteers and patients with torsion dystonia. Enzyme activities in erythrocytes from 14 patients with adult-onset, childhood-onset idiopathic, and childhood-onset familial dystonias did not differ significantly from activities measured in erythrocyte membranes from 17 healthy volunteers. Moreover, when blood samples from several members of a family with dominant inheritance of dystonia were assayed simultaneously, similar enzyme activities were found in the affected and unaffected individuals. The data suggest that a generalized acetylcholinesterase deficiency is not involved in the pathogenesis of torsion dystonia.

Acetylcholinesterase↗