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Biomedical subjects

S Fahn

Publications and source records attributed to S Fahn.

At least 37 records · Page 2Linked to original sources
PubMed2000

The spectrum of levodopa-induced dyskinesias.

The most common types of levodopa-induced dyskinesias in patients with Parkinson's disease (PD) are chorea and dystonia, and often the two types are intermixed. Myoclonus is a far less common problem. The dyskinesias tend to develop over time, not usually being encountered at the initiation of levodopa therapy. Eventually, they affect more than 50% of patients on long-term levodopa treatment. Once they appear, they are difficult to eliminate. Substituting weaker dopaminergic agents for levodopa often fails to eliminate the dyskinesias. Most of the dyskinesias occur at the time of the highest brain concentration of levodopa and its product, dopamine--so-called peak-dose dyskinesias. Chorea and dystonia, usually in the legs, occur less commonly at the beginning and end of dosing, and these are called diphasic dyskinesias. Dystonia can also occur during the 'off' state, i.e. when the levodopa concentration is low. These 'off' dystonias are often painful and must be distinguished from peak-dose dystonia and from dystonia that may be a feature of PD itself.

Dopamine Agents↗
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

The TOR1A (DYT1) gene family and its role in early onset torsion dystonia.

Most cases of early onset torsion dystonia are caused by a 3-bp deletion (GAG) in the coding region of the TOR1A gene (alias DYT1, DQ2), resulting in loss of a glutamic acid in the carboxy terminal of the encoded protein, torsin A. TOR1A and its homologue TOR1B (alias DQ1) are located adjacent to each other on human chromosome 9q34. Both genes comprise five similar exons; each gene spans a 10-kb region. Mutational analysis of most of the coding region and splice junctions of TOR1A and TOR1B did not reveal additional mutations in typical early onset cases lacking the GAG deletion (N = 17), in dystonic individuals with apparent homozygosity in the 9q34 chromosomal region (N = 5), or in a representative Ashkenazic Jewish individual with late onset dystonia, who shared a common haplotype in the 9q34 region with other late onset individuals in this ethnic group. A database search revealed a family of nine related genes (50-70% similarity) and their orthologues in species including human, mouse, rat, pig, zebrafish, fruitfly, and nematode. At least four of these genes occur in the human genome. Proteins encoded by this gene family share functional domains with the AAA/HSP/Clp-ATPase superfamily of chaperone-like proteins, but appear to represent a distinct evolutionary branch.

Adolescent↗
PubMed1999

Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole.

The authors report a new side effect of the dopamine agonists pramipexole and ropinirole: sudden irresistible attacks of sleep. Eight PD patients taking pramipexole and one taking ropinirole fell asleep while driving, causing accidents. Five experienced no warning before falling asleep. The attacks ceased when the drugs were stopped. Neurologists who prescribe these drugs and patients who take them should be aware of this possible side effect.

Aged↗
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↗
PubMed1998

Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.

Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease. Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics. Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon 10. The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10. This causes more frequent usage of the 5' splice site and an increased proportion of tau transcripts that include exon 10. The increase in exon 10+ messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17.

Alternative Splicing↗
PubMed1998

Functional brain networks in DYT1 dystonia.

Early-onset idiopathic torsion dystonia (ITD) is an autosomal dominant hyperkinetic movement disorder with incomplete penetrance, associated with a 3 base-pair deletion in the DYT1 gene on chromosome 9q34. To determine the metabolic substrates of brain dysfunction in DYT1 dystonia, we scanned 7 nonmanifesting and 10 affected DYT1 carriers and 14 normal volunteers with [18F]fluorodeoxyglucose and positron emission tomography. We found that DYT1 dystonia is mediated by the expression of two independent regional metabolic covariance patterns. The first pattern, identified in an analysis of nonmanifesting gene carriers was designated movement free (MF). This abnormal pattern was characterized by increased metabolic activity in the lentiform nuclei, cerebellum, and supplementary motor areas. The MF pattern was present in DYT1 carriers with and without clinical manifestations and persisted in DYT1 dystonia patients in whom involuntary movements were suppressed by sleep. The second pattern, identified in an analysis of affected gene carriers with sustained contractions at rest, was designated movement related (MR). This pattern was characterized by increased metabolic activity in the midbrain, cerebellum, and thalamus. The expression of the MR pattern was increased in waking DYT1 patients with sustained dystonia, compared with DYT1 carriers who were unaffected or who had dystonia only on action, as well as normal controls. MR subject scores declined significantly with sleep in affected DYT1 patients but not in normal controls. These findings indicate the penetrance of the DYT1 gene is considerably greater than previously assumed. ITD is mediated through the interaction of functional brain networks relating separately to gene status and to abnormal movement.

Adolescent↗