Gender ratio differences between Parkinson's disease patients and their affected relatives.

Mitochondrial dysfunction in Parkinson's disease (PD) is suspected to arise from either acquired or inherited mutation of mitochondrial DNA (mtDNA). If inherited, epidemiologic analysis may reveal maternal transmission. We looked for maternal inheritance bias in our PD clinical database. About 13% of 600 PD probands reported an affected parent. Although 60% of the PD probands were male, only 42% of the affected parents were. The gender ratios for the proband and affected parent generations were dissimilar (p<0.005), indicating an underrepresentation of affected fathers or an overrepresentation of affected mothers. To address these possibilities we analyzed a non-PD control cohort. Four percent of the controls had a PD affected parent, and 75% of these affected parents were male. Apparent maternal inheritance bias in our PD cohort is therefore more likely due to overrepresentation of affected mothers, and is consistent with mitochondrial inheritance in some of our ascertained cases.

Induction by dopamine D1 receptor agonist ABT-431 of dyskinesia similar to levodopa in patients with Parkinson disease.

BACKGROUND: Dyskinesias are a frequent adverse effect of long-term levodopa therapy. The relative contribution of dopamine D(1) and D(2) receptor function to the pathophysiology of levodopa-induced dyskinesias remains a matter of controversy. OBJECTIVE: To establish whether a selective D(1) dopamine agonist induces more or less dyskinesia than levodopa in primed dyskinetic patients with Parkinson disease. METHODS: We studied ABT-431, the prodrug of a fully selective D(1) agonist, in 20 subjects with advanced Parkinson disease and a fluctuating response to levodopa complicated by dyskinesias. Eight patients were studied in a double-blind, randomized design (French centers); 12, in an open, randomized design (US centers). We assessed and compared the antiparkinsonian (Unified Parkinson's Disease Rating Scale) and dyskinetic (response induced by an acute challenge of a suprathreshold dose of levodopa and by 4 different ascending doses (5, 10, 20, and 40 mg) of ABT-431 during the 6 hours after the challenge. RESULTS: The separate analysis of the double-blind and open data led to the same findings, ie, the antiparkinsonian and dyskinetic responses induced by ABT-431 were dose related. At the most effective doses (20 and 40 mg), ABT-431 exhibited similar antiparkinsonian benefit and produced similar dyskinesias as levodopa. CONCLUSION: Dopamine D(1) agonists can induce a full antiparkinsonian response but do not support previous hypotheses suggesting that D(1) agonists are more or less likely to produce dyskinesias than levodopa.

Early changes in neuropeptide mRNA expression in the striatum following reserpine treatment.

Chronic dopamine depletion produces neurochemical changes within the striatum as well as enhanced behavioral and metabolic responses to dopamine agonists. Changes in striatal neuropeptides have been consistently described, including increased expression of preproenkephalin mRNA and decreased expression of preprotachykinin and prodynorphin mRNA. Acute dopamine depletion following treatment with reserpine also produces enhanced behavioral and metabolic responses to agonist treatment which develop rapidly. In the present study, we used in situ hybridization histochemistry to investigate whether acute neurochemical changes occur following reserpine treatment. We evaluated neuropeptide mRNA expression in the striatum and nucleus accumbens at several time points from 6 to 120 h following single doses of reserpine and AMPT. The aim of these studies was to determine if changes in neuropeptide mRNA expression occur following acute dopamine depletion and whether such changes are specific to the striatum. Changes in striatal neuropeptide mRNA expression developed rapidly. Preproenkephalin mRNA expression by striatopallidal neurons was unchanged at 48 h, but increased by 44% at 120 h. Preprotachykinin mRNA expression in striatonigral neurons was increased at 6 h and then fell, with a maximal decrease of 45% at 48 h and partial recovery by 120 h. Prodynorphin mRNA expression was unchanged. Expression of preproenkephalin and preprotachykinin mRNA was also examined in subregions of the striatum and the nucleus accumbens. Expression of preproenkephalin mRNA was uniform in the striatum and higher in the core than the shell of the nucleus accumbens. Preprotachykinin mRNA expression in the striatum was higher in the lateral quadrants and was higher in the shell than in the core of the nucleus accumbens. The changes in neuropeptide mRNA following treatment with reserpine were only found in the striatum. These data provide further evidence for early alterations in neuronal function in the striatum following acute dopamine depletion and suggest that neuropeptide expression by striatonigral neurons may be more rapidly regulated in response to changes in dopamine levels.

Dopa-responsive dystonia due to a large deletion in the GTP cyclohydrolase I gene.

Although it is assumed that most patients with autosomal dominant dopa-responsive dystonia (DRD) have a GTP cyclohydrolase I dysfunction, conventional genomic DNA sequencing of the gene (GCH1) coding for this enzyme fails to reveal any mutations in about 40% of DRD patients, which makes molecular genetic diagnosis difficult. We found a large heterozygous GCH1 deletion, which cannot be detected by the usual genomic DNA sequence analysis, in a three-generation DRD family and conclude that a large genomic deletion in GCH1 may account for some "mutation-negative" patients with dominantly inherited DRD.

Early morning dystonia in Parkinson's disease.

We interviewed 383 patients with PD regarding disease onset and medication history and evaluated them using the Unified Parkinson's Disease Rating Scale. Sixteen percent of the sample reported the occurrence of early morning dystonia (EMD). Patients with EMD had been taking levodopa for a longer time, were taking higher daily levodopa doses, demonstrated more disability in carrying out their activities of daily living, exhibited dystonia more often before initiation of levodopa treatment, and experienced more peak-dose and diphasic dyskinesias with levodopa therapy.

Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations.

Mutations in the GTP-cyclohydrolase I (GCH) gene have been identified as a cause of two disorders: autosomal dominant hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD) and autosomal recessive GCH-deficient hyperphenylalaninemia (HPA). Detailed clinical descriptions and genetic analysis of patients with phenotypes intermediate between HPD/DRD (mild) and GCH-deficient HPA (severe) have not been reported. We conducted genomic DNA sequencing of the GCH gene in two patients (Cases 1 and 2) manifesting generalized dystonia responsive to levodopa and severe developmental motor delay. In the pedigree of Patient 1, there were HPD/DRD patients in three generations preceding the index case. Patients 1 and 2 were compound heterozygotes with maternally and paternally transmitted mutations in the coding region of the GCH gene. In both compound heterozygotes, tetrahydrobiopterin (BH4) levels in cerebrospinal fluid were lower than those in HPD/DRD. Administration of BH4, in addition to levodopa, further improved the symptomatology of Patient 1. Our data demonstrate a new phenotype of GCH deficiency associated with compound heterozygosity for GCH gene mutations and suggest the usefulness of combined BH4 and levodopa therapy for this disorder.

Gender-related penetrance and de novo GTP-cyclohydrolase I gene mutations in dopa-responsive dystonia.

We evaluated the influence of gender on penetrance of GTP-cyclohydrolase I (GCH) gene mutations in hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD) and determined whether some apparently sporadic HPD/DRD patients owe their disorder to a de novo mutation of the GCH gene. Previous clinical investigations of HPD/DRD have shown a predominance of affected women, with approximately half of HPD/DRD patients being sporadic. We conducted genomic DNA sequencing of the GCH gene in five HPD/DRD families having at least two generations of affected members and in four apparently sporadic cases and all of their parents. In the nine HPD/DRD pedigrees, we found independent mutations of the GCH gene (five deletions, one insertion, one nonsense mutation, and two point mutations at splice acceptor sites). The female-to-male ratio of the HPD/DRD patients was 4.3 with the penetrance of GCH gene mutations in women being 2.3 times higher than that in men (87% versus 38%, p = 0.026). There was no significant difference in the penetrance between maternally and paternally transmitted offspring. All of the four sporadic cases had de novo mutations because none of their parents were carriers. The results demonstrate gender-related incomplete penetrance of GCH gene mutations in HPD/DRD and suggest that this may not be due to genomic imprinting. Our data also suggest a relatively high spontaneous mutation rate of the GCH gene in this autosomal dominant disorder.

Oral phenylalanine loading in dopa-responsive dystonia: a possible diagnostic test.

To determine if there is abnormal phenylalanine and biopterin metabolism in patients with dopa-responsive dystonia (DRD), we measured plasma levels of phenylalanine, tyrosine, biopterin, and neopterin at baseline, and 1, 2, 4, and 6 hours after an oral phenylalanine load (100 mg/kg). Seven adults with DRD, two severely affected children with DRD, and nine adult controls were studied. All patients had phenylalanine and tyrosine concentrations within the normal range at baseline. In the adult patients, phenylalanine levels were higher than in controls at 2, 4, and 6 hours post-load (p < 0.0005); tyrosine concentrations were lower than control levels at 1, 2, and 4 hours post-load (p < 0.05). Phenylalanine to tyrosine ratios were elevated in patients at all times post-load (p < 0.0005). Biopterin levels in the patients were decreased at baseline and 1, 2, and 4 hours post-load (p < 0.005). Pretreatment with tetrahydrobiopterin (7.5 mg/kg) normalized phenylalanine and tyrosine profiles in two adult patients. In the children with DRD, phenylalanine to tyrosine ratios were slightly elevated at baseline. Following phenylalanine loading, the phenylalanine profiles were similar to those seen in the adult patients but there was no elevation in plasma tyrosine. Baseline biopterin levels were lower in the children with DRD than in the adult patients or the controls and there was no increase in biopterin post-load. In both the children and adults with DRD, neopterin concentrations did not differ from control values at baseline or after phenylalanine load. The results are consistent with decreased liver phenylalanine hydroxylase activity due to defective synthesis of tetrahydrobiopterin in patients with DRD. The findings show that a phenylalanine load may be useful in the diagnosis of this disorder.

Clinical correlates of sleep benefit in Parkinson's disease.

The phenomenon of sleep benefit, a period of lessened disability or feeling "on" upon awakening from sleep in the morning, has received scant attention in the literature on Parkinson's disease. We interviewed 162 consecutive patients regarding disease onset, medication history, and symptoms, evaluated them using the Unified Parkinson's Disease Rating Scale, and assessed them as to the presence or absence of sleep benefit. Thirty-three percent reported experiencing sleep benefit. Compared with patients not having sleep benefit, patients with sleep benefit tended to be younger at disease onset, have longer disease duration, take higher total daily doses of levodopa, have longer duration of levodopa treatment, and exhibit less cognitive and physical disability. The findings of this study suggest that sleep benefit is a common phenomenon that may be anticipated in a subgroup of patients with Parkinson's disease. The mechanisms underlying sleep benefit do not appear to be simple and may be multifactorial. Clinicians need to be aware of the authenticity of patients' reports of sleep benefit and consider the existence of this phenomenon when prescribing or adjusting patients' medication schedules.

Maternal inheritance in Parkinson's disease.

To evaluate possible matrilineal factors in the inheritance of Parkinson's disease, we prospectively identified families in which a parent and multiple siblings had Parkinson's disease. In each of the 5 families identified, the affected parent was the mother (p < 0.03). The age at onset in the offspring generation in these 5 families was younger than the age at onset in the parental generation (p < 0.001). In addition, the age at onset in all patients with an affected mother (n = 18) was younger than the age at onset in the affected mothers (p < 0.001). No difference was found between the age at onset in patients with an affected father (n = 14) and the age at onset in the affected fathers. These results are consistent with a role for inherited abnormalities of mitochondrial DNA in the pathogenesis of at least some cases of Parkinson's disease.

Dose-related effects of continuous levodopa infusion in rats with unilateral lesions of the substantia nigra.

Preclinical studies in rats have demonstrated markedly different effects of intermittent and continuous levodopa administration on many biochemical and functional parameters yet the dose regimens employed have not been fully evaluated. In this study, rats with unilateral 6-hydroxydopamine nigral lesions were administered levodopa (0-1200 mg/kg/day) and benserazide (25 mg/kg/day) subcutaneously via osmotic minipump and studied 20-22 h later for rotational behavior, striatal dopamine concentration, and regional cerebral glucose utilization (RCGU). Levodopa infusion at 100 mg/kg/day resulted in minimal rotation and minimal striatal dopamine replacement but did increase RCGU in the subthalamic nucleus and decrease RCGU in the lateral habenula, consistent with a selective inhibition of the striatopallidal GABAergic (indirect striatal output) pathway. Levodopa infusion at 100 mg/kg/day did not significantly increase RCGU in the entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr), as does the acute injection of levodopa (25-50 mg/kg), indicating that this levodopa dose elicits only part of the spectrum of metabolic effects elicited by acute levodopa injection. Higher doses of levodopa (400-1200 mg/kg/day) resulted in moderate rates of rotation, dose-dependent increases in striatal dopamine, and increased RCGU in the EP and SNr, consistent with activation of the striatonigral GABAergic (direct striatal output) pathway. In the EP and SNr, the two major output nuclei of the basal ganglia, levodopa infusion at 800 and 1200 mg/kg/day reproduced the metabolic effects elicited by acute injection of levodopa. These results demonstrate, for the first time, dose-dependent effects of levodopa on distinct populations of striatal output neurons which may be relevant to the pathogenesis of levodopa-induced dyskinesias in Parkinson's disease. The minimal dopamine replacement and partial functional effects elicited by levodopa infusion at 100 mg/kg/day indicate the need for caution in the interpretation of prior studies of continuous levodopa infusion which employed this dose.

D1/D2 actions of dopaminergic drugs studied with [14C]-2-deoxyglucose autoradiography.

1. To define the neural circuits activated by dopaminergic stimulation in rat models of parkinsonism, the author studied the effects of L-dopa and selective D1 and D2 agonists on RCGU in rats with unilateral 6-OHDA substantia nigra lesions. 2. Systemic administration of L-dopa markedly increased RCGU in the EP and SNr ipsilateral to the nigral lesions; it is suggested that this represents metabolic activity primarily in axon terminals of GABAergic striatal projection neurons. These effects were reproduced by selective D1, but not D2, dopamine agonists, and were blocked completely by a D1 antagonist, indicating their critical dependence on D1 stimulation. L-dopa moderately increased RCGU in the STN; this effect was reproduced by D1 and D2 agonists and was blocked completely only by combined D1 and D2 antagonist pretreatment. 3. The RCGU data support a direct stimulatory action of dopamine, formed from L-dopa, on D1 receptor-bearing striatal GABAergic neurons projecting to the EP and SNr as well as a net stimulatory action on the GP output to the STN. 4. The marked D1-mediated RCGU increase in the SNr ipsilateral to the dopamine depletion contrasts with the modest increase seen on the contralateral side and in naive rats, suggesting that the enhanced RCGU response to D1 stimulation is an index of dopaminergic supersensitivity. The stimulatory effect of the D1 agonist SKF 38393 on RCGU in the SNr is enhanced 6-12 hours after acute dopamine depletion with reserpine/AMPT indicating that supersensitive responses develop within this rapid time frame. 5. The RCGU data indicate that D1 receptor stimulation contributes importantly, in an anatomically selective manner, to the effects of L-dopa on basal ganglia circuits and that the response to D1 stimulation is rapidly modifiable by dopamine depletion.

Exclusion of the DYT1 locus in a non-Jewish family with early-onset dystonia.

The DYT1 gene on chromosome 9q34 underlies idiopathic torsion dystonia (ITD) in Jewish and non-Jewish families with childhood and adolescent-onset dystonia that usually starts in a limb, spreads to other limbs, and uncommonly involves cranial muscles. We examined 39 members of a Mennonite family of German ancestry in which seven were affected with ITD. Age at onset was 14.7 years (range 5-34 years) and symptoms began in a limb in four. The remaining three had onset in the neck, face, and larynx. Dystonia progressed to involve at least one arm and one leg in all seven and there was cranial involvement in six. Five of these six had moderate or severe speech impairment. Linkage analysis with 9q34 markers excluded the region containing the DYT1 locus in this family. This study suggests that a gene other than DYT1 underlies some cases of early limb-onset ITD. The clinical features of prominent cranial involvement and impaired speech distinguish this "non-DYT1" early-onset ITD family from the typical DYT1 phenotype.

Treatment of severe axial tardive dystonia with clozapine: case report and hypothesis.

We report a patient with severe axial tardive dystonia who has had dramatic improvement for 4 years after treatment with the atypical antipsychotic drug clozapine (625 mg/day). Clozapine differs from conventional neuroleptics in that it has higher affinity for D1 and lower affinity for D2 dopamine receptors than do conventional antipsychotics, which are relatively selective D2 antagonists. We propose that repetitive stimulation of the D1 receptor by endogenous dopamine, resulting in sensitization of the D1-mediated striatal output in the presence of D2 receptor blockade, is a fundamental mechanism mediating tardive dyskinesia, including the dystonic type. According to this hypothesis, it is primarily the D1 antagonist action of clozapine that accounts for its inability to cause tardive dyskinesia as well as its therapeutic effect in tardive dystonia. Regardless of its mechanism of action, the sustained improvement observed in this case suggests that clozapine should be tried in cases of severe refractory tardive dystonia.

Linkage mapping of dopa-responsive dystonia (DRD) to chromosome 14q.

Dopa-responsive dystonia (DRD) is an autosomal-dominant neurological disorder which appears to result from a genetically determined deficiency of striatal dopamine. Pathological evidence suggests that this may be due to the establishment of a reduced number of dopaminergic nerve terminals in the striatum, or to an excessive reduction (pruning) of these terminals in early development. We have mapped the DRD gene to chromosome 14 by linkage analysis in 3 families with a maximum 2-point lod score of 4.67 at 8.6 centiMorgans from D14S63; maximum multipoint lod scores > 6 were obtained for the intervals D14S47-D14S52 and D14S52-D14S63. The flanking loci D14S47 and D14S63 define a region of about 22 cM as containing the DRD gene.

Reversal of reserpine-induced catalepsy by selective D1 and D2 dopamine agonists.

To gain insight into the antiparkinsonian effects of selective D1 and D2 dopamine receptor stimulation, we examined the ability of D1 (SKF 38393) and D2 (quinpirole) agonists to reverse catalepsy induced by the combined administration of reserpine and alpha-methyl-p-tyrosine (AMPT) in rats. Catalepsy, the failure to correct an externally imposed posture, is a measure of akinesia and was assessed using the bar test. Rats injected with reserpine alone (2.5 mg/kg i.p.) developed akinesia and ptosis within 60-90 min. The D1 agonist SKF 38393 (30 mg/kg i.v.) rapidly reversed ptosis and restored near-normal mobility when administered 24 h after reserpine and AMPT; catalepsy was reversed for 90 min, after which the drug effect wore off. Quinpirole (1 mg/kg i.v.) reversed catalepsy for the duration of the test period (4 h) but did not consistently reverse ptosis or promote normal mobility; the rats continued to exhibit kyphotic postures with little spontaneous locomotion. These results indicate that selective D1 stimulation is sufficient to reverse reserpine-induced akinesia and highlight the need for the development of potent selective D1 agonists for clinical trial in Parkinson's disease. In severe dopamine depletion, D2 stimulation alone appears to be insufficient to restore normal movement. Quinpirole, but not SKF 38393, elicited paroxysmal limb/body jerking in reserpine-AMPT-treated rats, providing further evidence that atypical jerking can be elicited by D2 stimulation in the complete absence of D1 stimulation. This laboratory observation suggests that some jerking dyskinesias seen in treated parkinsonian patients may be mediated by an imbalance in D1-D2 receptor stimulation.