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Biomedical subjects

S Fahn

Publications and source records attributed to S Fahn.

At least 19 recordsLinked to original sources
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↗
PubMed1998

Experience with tranylcypromine in early Parkinson's disease.

A leading hypothesis of the pathogenesis of neuronal degeneration of the substantia nigra dopamine-containing cells in Parkinson's disease (PD) is excessive oxidative stress. In part, this oxidative stress is the result of the oxidation of dopamine by the action of monoamine oxidases (MAO) A and B to generate hydrogen peroxide and subsequent oxygen free radicals. Because of this hypothesis we have treated patients with early PD, not yet requiring any symptomatic treatment, with tranylcypromine, a drug that inhibits both MAO's. These patients were required to observe a tyramine-restricted diet. Thirty-seven patients on tranylcypromine have been followed by us for up to 33 months. Four patients discontinued the drug because of pending surgery. Of the remaining 33, six had adverse effects that lead to discontinuation of the drug, mainly impotency in men. Another common adverse effect encountered was insomnia, but this problem was not a cause of stopping the drug. Depression lifted in all five patients who had this problem at the time tranylcypromine was initiated. Only two patients have so far required treatment with levodopa or a dopamine agonist, and this need occurred within the first 6 months of treatment. The evaluation of all 37 patients revealed that parkinsonian symptoms improved slightly on introduction of tranylcypromine as measured by the United Parkinson's Disease Rating Scale, the Hoehn & Yahr Staging Scale, and the Schwab & England Activities of Daily Living Scale. Follow-up evaluations for a minimum of 6 months between the first post-tranylcypromine visit and the most recent visit revealed only slight worsening of parkinsonian signs and symptoms, with a mean interval of almost 1.5 years. A longer period of follow-up is needed to determine how long the severity of PD will remain mild in this group of patients.

Adult↗
PubMed1998

Current concepts on the clinical features, aetiology and management of idiopathic cervical dystonia.

Idiopathic cervical dystonia (ICD) is the most common form of adult-onset focal dystonia. Previously, disagreement existed about whether ICD was a psychiatric illness, but the disorder is now viewed as a neurological illness and large clinical series have clarified the clinical features of the disease. At the time of diagnosis, extracervical dystonia is found in approximately 20% of patients, and there may be a concomitant head or hand tremor. Importantly, adult-onset ICD does not become generalized, although there may be segmental spread and pain may increase independently of the dystonia. While 10-20% of patients may experience remission, nearly all patients relapse within 5 years and are left with persistent disease. The aetiology of ICD is unknown, but there has been much progress in clarifying the genetic abnormality in families with inherited adult-onset cervical dystonia; linkage to chromosome 18p has been demonstrated in one family, and the DYT1 locus has been excluded in two other families. Painful trauma may be involved in the pathogenesis of ICD. Painful stimuli are received and processed by the basal ganglia, and the synaptic changes provoked by pain may lead to the abnormal physiology underlying dystonia. Consistent with this idea are experiments which demonstrate that altered sensory input leads to plasticity of the motor cortex, and those that explore the 'tonic vibration reflex' in patients with dystonia. Another theory suggests that a primary vestibular abnormality is responsible for ICD. Botulinum toxin is the most effective treatment for ICD. Roughly 75% of patients improve, and a response is generally seen within the first week. However, many questions remain regarding the optimal technique of administration. The development of neutralizing antibodies occurs in at least 5-10% of patients, and appears to be related both to dosage and to the interval between treatments. Side-effects are generally mild and result from the action of the toxin in the periphery. If the response to botulinum toxin is not adequate, anticholinergics, benzodiazepines, baclofen and other medications are used as adjunctive therapy. Surgical therapies are available for the treatment of ICD but are reserved for patients refractory to conservative measures.

Diagnosis, Differential↗
PubMed1998

Fetal tissue transplantation [correction of transplanation] in Parkinson's disease.

Since the first successful attempts in 1990, human embryonic tissue transplantation has attracted the attention of multiple investigators and clinicians as a serious candidate therapy for Parkinson's disease. Although over two hundred patients have undergone the procedure, multiple issues and questions remain unresolved. We will address this topic emphasizing the recent advances in the technical aspects of the transplantation procedure in light of the limited animal and clinical experience available.

Cell Survival↗