Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia.

OBJECTIVE: To identify the cause of childhood onset involuntary paroxysmal choreiform and dystonic movements in 2 unrelated sporadic cases and to investigate the functional effect of missense mutations in adenylyl cyclase 5 (ADCY5) in sporadic and inherited cases of autosomal dominant familial dyskinesia with facial myokymia (FDFM). METHODS: Whole exome sequencing was performed on 2 parent-child trios. The effect of mutations in ADCY5 was studied by measurement of cyclic adenosine monophosphate (cAMP) accumulation under stimulatory and inhibitory conditions. RESULTS: The same de novo mutation (c.1252C>T, p.R418W) in ADCY5 was found in both studied cases. An inherited missense mutation (c.2176G>A, p.A726T) in ADCY5 was previously reported in a family with FDFM. The significant phenotypic overlap with FDFM was recognized in both cases only after discovery of the molecular link. The inherited mutation in the FDFM family and the recurrent de novo mutation affect residues in different protein domains, the first cytoplasmic domain and the first membrane-spanning domain, respectively. Functional studies revealed a statistically significant increase in ß-receptor agonist-stimulated intracellular cAMP consistent with an increase in adenylyl cyclase activity for both mutants relative to wild-type protein, indicative of a gain-of-function effect. INTERPRETATION: FDFM is likely caused by gain-of-function mutations in different domains of ADCY5-the first definitive link between adenylyl cyclase mutation and human disease. We have illustrated the power of hypothesis-free exome sequencing in establishing diagnoses in rare disorders with complex and variable phenotype. Mutations in ADCY5 should be considered in patients with undiagnosed complex movement disorders even in the absence of a family history.

Nicotine from edible Solanaceae and risk of Parkinson disease.

OBJECTIVE: To test whether risk of Parkinson disease (PD) is associated with consumption of nicotine-containing edibles from the same botanical family as tobacco, Solanaceae, including peppers, tomatoes, and potatoes. METHODS: In a population-based study with 490 newly diagnosed idiopathic PD cases diagnosed during 1992-2008 at the University of Washington Neurology Clinic or Group Health Cooperative in western Washington State and 644 unrelated, neurologically normal controls, we examined whether PD was associated with self-reported typical frequency of consumption of peppers, tomatoes, tomato juice, and potatoes during adulthood, while adjusting for consumption of other vegetables, age, sex, race/ethnicity, tobacco use, and caffeine. RESULTS: PD was inversely associated with consumption of all edible Solanaceae combined (relative risk [RR] = 0.81, 95% confidence interval [CI] = 0.65-1.01 per time per day), but not consumption of all other vegetables combined (RR = 1.00, 95% CI = 0.92-1.10). The trend strengthened when we weighted edible Solanaceae by nicotine concentration (ptrend = 0.004). An inverse association was also evident for peppers specifically (ptrend = 0.005). The potentially protective effect of edible Solanaceae largely occurred in men and women who had never used tobacco or who had smoked cigarettes < 10 years. INTERPRETATION: Dietary nicotine or other constituents of tobacco and peppers may reduce PD risk. However, confirmation and extension of these findings are needed to strengthen causal inferences that could suggest possible dietary or pharmaceutical interventions for PD prevention.

Formulations of hormone therapy and risk of Parkinson's disease.

Hormone therapy (HT) is a class of medications widely prescribed to women in the Western world. Evidence from animal models and in vitro studies suggests that estrogen may protect against nigrostriatal system injury and increase dopamine synthesis, metabolism, and transport. Existing epidemiologic research indicates a possible reduced risk of Parkinson's disease (PD) associated with HT use. The objective of this study was to evaluate PD risk associated with specific HT formulations. Neurologist-confirmed cases and age-matched controls were identified from Group Health Cooperative (GHC) of Washington State. Final analysis included 137 female cases and 227 controls. Hormone therapy use was ascertained from the GHC pharmacy database, further classified as conjugated estrogens, esterified estrogens, and progestin. Ever use of HT formulation demonstrated a suggested elevated risk with esterified estrogen use (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.0-9.8), and no risk associated with conjugated estrogen use (OR, 0.6; 95% CI, 0.6-1.3). Restricting this analysis to prescriptions that included progestin further elevated the risk associated with esterified estrogen use (OR, 6.9; 95% CI, 2.1-22.9); again, no risk was associated with conjugated estrogen use (OR, 1.7; 95% CI, 0.6-5.0). The findings from this study suggest an increase in PD risk associated with esterified estrogen use combined with progestin, and no risk associated with conjugated estrogen with progestin. These findings could have important implications for choice of HT in clinical practice.

Environmental tobacco smoke and Parkinson's disease.

BACKGROUND: Parkinson's disease is inversely associated with cigarette smoking, but its relation with passive smoking or environmental tobacco smoke exposure is rarely examined. METHODS: Within a case-control study, we assessed the association between Parkinson's disease and living or working with active smokers. Cases were newly diagnosed with idiopathic Parkinson's disease (n = 154) from western Washington State in 2002-2008. Age- and sex-matched controls (n = 173) were neurologically normal and unrelated to cases. RESULTS: Compared with never active or passive tobacco smokers, we observed reduced Parkinson's disease risks for ever passive only smokers (OR, 0.34; 95% CI, 0.16-0.73), similar to those for ever active smokers (OR, 0.35; 95% CI, 0.17-0.73). Among persons whose only tobacco smoke exposure was passive smoking at home, risk was inversely associated with years exposed. CONCLUSIONS: These observations parallel those well established for active smoking. However, it remains unresolved whether a true protective effect of tobacco smoke, generally detrimental to health, underlies these associations.

Occupational factors and risk of Parkinson's disease: A population-based case-control study.

BACKGROUND: Parkinson's disease (PD) has been associated with various workplace factors, but the evidence is inconsistent. OBJECTIVE: To estimate the risk of PD associated with various jobs and workplace exposures. METHODS: We conducted a population-based, case-control study of 404 incident PD cases and 526 age and sex-matched controls, collecting self-reported work histories including job titles and exposures to various industrial toxicants. Relative risks of PD from these exposures were estimated with odds ratios (OR) and 95% confidence intervals (CI) using logistic regression. RESULTS: Risk was not significantly affected by farming work, by metal work, or by exposure to pesticides, metals, or solvents. CONCLUSIONS: These findings do not provide support for the hypothesis that workplace factors affect the risk of PD.

Dietary fats, cholesterol and iron as risk factors for Parkinson's disease.

BACKGROUND: Epidemiologic findings suggest that dietary components may contribute to the etiology of Parkinson's disease (PD). This population-based case-control study evaluated PD risk and dietary intake of fats, cholesterol and iron. METHODS: Newly diagnosed case (n=420) and age/gender/ethnicity-matched unrelated controls (n=560) were identified between 1992 and 2006 from the Group Health Cooperative health maintenance organization in western Washington State, and the University of Washington Neurology Clinic. In-person interviews elicited data on food frequency habits during most of adult life. Nutritional intakes were calculated and analyzed, with adjustments made for total energy intake (the 'nutrition density' technique). RESULTS: Cholesterol intake in the highest quartile compared with the lowest quartile was associated with a decreased risk of PD in men (odds ratio (OR)=0.53, 95%CI: 0.33, 0.86). The highest versus the lowest quartile of dietary iron increased PD risk in men (OR=1.82, 95%CI: 1.11, 2.99). When the lowest quartile of cholesterol and the highest quartile for iron were compared to the highest quartile of cholesterol and the lowest quartile of iron, no association was seen in women, but for men PD risk was increased (OR=2.70, 95%CI: 1.26, 5.76). Saturated fat intake below the median in combination with iron intake above the median also increased the PD risk (OR=1.50, 95%CI: 1.07, 2.11) in both genders combined. CONCLUSIONS: A low intake of cholesterol, particularly in the presence of high iron, may be associated with an increased risk for PD.

The functional polymorphism of the hemoglobin-binding protein haptoglobin influences susceptibility to idiopathic Parkinson's disease.

Oxidative stress and iron have been widely implicated in the etiology of Parkinson's disease (PD). Hemoglobin is the richest source of iron in the body. The human Haptoglobin (Hp) protein is a plasma alpha-2 glycoprotein that removes free Hemoglobin from the circulation and tissues and is important in protection from oxidative stress, in immune system regulation, and angiogenesis. A common genetic polymorphism of Hp exists in the population, where the Hp 1-1, Hp 2-1, and Hp 2-2 forms exhibit profound functional differences. In this study, the Hp genotype corresponding to phenotypes Hp 1-1, 2-1 and 2-2 was determined in 312 idiopathic PD patients and 420 normal control subjects. A significant increase in the number of subjects carrying the Hp 2-1 genotype was present among PD patients. The distribution of Hp genotypes among PD patients (16.0% Hp 1-1, 56.4% Hp 2-1, 27.6% Hp 2-2) was significantly different from the distribution in controls (15.2% Hp 1-1, 48.1% Hp 2-1, 36.7% Hp 2-2) (chi(2) = 6.99, P = 0.030). The odds ratios for PD risk for Hp 2-1 and Hp 1-1 versus Hp 2-2 genotype were 1.51 (1.07-2.12) and 1.36 (0.86-2.15), respectively. Overall, the association of Hp-1 allele with PD resulted stronger among subjects who were never-smokers as compared to ever-smokers. Also, among ever-smokers, Hp genotypes were significantly associated with PD only among women, but not men, indicating the presence of a gene x gender x smoking interaction. To our knowledge, this is the first study that investigates the association of Hp genotypes with the risk of PD.

Calcium channel blockers and beta-blockers in relation to Parkinson's disease.

We investigated the risk of Parkinson's disease (PD) associated with calcium channel blockers (CCBs) and beta-blockers in a population-based case-control study of 206 men and women between ages 35 and 89 with a new diagnosis of idiopathic PD between 1992 and 2002, and 383 controls without PD or other neurodegenerative disorders who were frequency matched on age, sex, duration of GHC enrollment and clinic. The adjusted odds ratio associated with ever use was 0.85 (95% confidence interval [CI]: 0.43, 1.66) for CCBs, and 1.20 (95% CI: 0.71, 2.03) for beta-blockers. We observed no association with PD risk for either class of medication in terms of duration, dose, number of prescriptions or pattern of use. The weakness of these associations and the absence of additional influence of dose or duration of use argue against any causal interpretation.

Chaos theory and the treatment of refractory status epilepticus: Who benefits from prolonged anesthesia, and is there a better way?

Refractory status epilepticus (SE) is a condition of continuous seizure activity in which there is a regular, rapid, succession of spike discharges in the brain. It is incompatible with normal consciousness and is associated with an extremely high morbidity and mortality. Prior to 1990, prevailing opinion held that a brief period of anesthesia (up to two weeks) was to be recommended, but that if SE persisted this was a sign of irreversible brain damage. Therefore support of the patient in SE was not recommended beyond two weeks. On the basis of the theoretical constructs of chaos theory we hypothesized that, for selected cases, anesthesia should be continued indefinitely until the SE resolved. This became the standard of care at the University of Washington and at other institutions. After several years, the accumulating evidence lends support for this hypothesis and we are now able to propose which patients will benefit from such therapy. It is hypothesized that only those patients for whom there is no underlying brain disease, beyond epilepsy, are likely to benefit. Secondly, chaos theory suggests that a strong perturbation will cause a rapid transition from the stable attractor of SE to the stable attractor representing normal consciousness. In certain ways, SE is analogous to ventricular tachycardia, where the cardiac muscle has an abnormally fast rhythm incompatible with proper cardiac function. Therefore the second hypothesis is that a brain perturbation, analogous to defibrillation, may be even more useful than anesthesia in refractory SE.

Diabetes, smoking, and other medical conditions in relation to Parkinson's disease risk.

Associations of Parkinson's disease (PD) with diabetes mellitus (DM) and other medical conditions were investigated in a case-control study of 352 newly diagnosed PD case and 484 control subjects. Men with DM had a significantly lower risk of PD, than men without DM (odds ratio (OR) = 0.52, 95% confidence interval (CI) = 0.28, 0.97), whereas the association in women was weaker (OR = 0.80, 95% CI = 0.35, 1.83). PD risk was reduced among male and female smokers, with and without diabetes. However, among diabetics, the PD risk was especially reduced in non-smoking men (OR = 0.09, 95% CI = 0.02, 0.44). Other medical conditions showed no strong relations with PD.

No associations between Parkinson's disease and polymorphisms of the quinone oxidoreductase (NQO1, NQO2) genes.

Reactive oxygen species derived from dopamine metabolism can induce oxidative stress and thus may contribute to Parkinson's disease (PD) pathogenesis. The quinone oxidoreductases, nicotinamide adenine dinucleotide (phosphate) (NAD[P]H): quinone oxidoreductase 1 (NQO1) and dihydronicotinamide riboside (NRH): quinone oxidoreductase 2 (NQO2) detoxify quinones and quinonoid compounds. We investigated associations of genetic polymorphisms of NQO1 (C609T) and NQO2 (I/D, 29 base pairs) with PD in a population-based case-control study of 190 idiopathic PD cases and 305 unrelated controls matched on age and sex. No associations were detected for either gene variant or for any allele combinations.

ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations.

OBJECTIVE: To investigate the clinical spectrum and distinguishing features of adenylate cyclase 5 (ADCY5)-related dyskinesia and genotype-phenotype relationship. METHODS: We analyzed ADCY5 in patients with choreiform or dystonic movements by exome or targeted sequencing. Suspected mosaicism was confirmed by allele-specific amplification. We evaluated clinical features in our 50 new and previously reported cases. RESULTS: We identified 3 new families and 12 new sporadic cases with ADCY5 mutations. These mutations cause a mixed hyperkinetic disorder that includes dystonia, chorea, and myoclonus, often with facial involvement. The movements are sometimes painful and show episodic worsening on a fluctuating background. Many patients have axial hypotonia. In 2 unrelated families, a p.A726T mutation in the first cytoplasmic domain (C1) causes a relatively mild disorder of prominent facial and hand dystonia and chorea. Mutations p.R418W or p.R418Q in C1, de novo in 13 individuals and inherited in 1, produce a moderate to severe disorder with axial hypotonia, limb hypertonia, paroxysmal nocturnal or diurnal dyskinesia, chorea, myoclonus, and intermittent facial dyskinesia. Somatic mosaicism is usually associated with a less severe phenotype. In one family, a p.M1029K mutation in the C2 domain causes severe dystonia, hypotonia, and chorea. The progenitor, whose childhood-onset episodic movement disorder almost disappeared in adulthood, was mosaic for the mutation. CONCLUSIONS: ADCY5-related dyskinesia is a childhood-onset disorder with a wide range of hyperkinetic abnormal movements. Genotype-specific correlations and mosaicism play important roles in the phenotypic variability. Recurrent mutations suggest particular functional importance of residues 418 and 726 in disease pathogenesis.

Glutathione S-transferase M1, T1, and P1 polymorphisms and Parkinson's disease.

Oxidative stress is widely thought to contribute significantly to the pathogenesis Parkinson's disease (PD). Given the role of glutathione S-transferases (GSTs) in the conjugation of electrophiles and protection against reactive oxygen species, genes encoding the GSTs have been considered candidates for association studies of PD. We tested for associations between genotypes of GSTM1(homozygous deletion vs. non-deleted), GSTT1(homozygous deletion vs. non-deleted), and GSTP1 (Ile104Val and Ala113Val) and PD in a case-control study of 214 idiopathic PD cases and 330 age- and gender-matched, unrelated controls of Caucasian ethnicity. No significant associations with any of the GST genotypes were observed. However, there was a marginally significant difference in the distribution of GSTP1 104 genotypes between cases and controls (P=0.07), with an excess of Ile104Val heterozygotes found among cases (odds ratio (OR)=1.43; 95% Confidence Interval (CI): 0.98-2.08). This difference in the genotype distribution was strongest among smokers (OR for heterozygote=1.92; 95% CI: 1.12-3.29) versus non-smokers and among males (OR for heterozygote=1.99; 95% CI: 1.24-3.19) versus females. The distribution of GSTP1 Ile104Val and Ala113Val haplotypes did not differ between cases and controls. Taken together, these results suggest a potentially minor role of GSTP1 in PD, but do not give evidence for associations with either GSTM1 or GSTT1.

Gender difference in the interaction of smoking and monoamine oxidase B intron 13 genotype in Parkinson's disease.

We tested for gender-specific interactions between smoking and genetic polymorphisms of monoamine oxidase B (MAO-B) intron 13 (G or A allele), monoamine oxidase A (MAO-A) EcoRV (Yor N allele), and dopamine D2 recepor (DRD2) Taq1B (B1 or B2 allele) in a case-control study of 186 incident idiopathic Parkinson's disease (PD) cases and 296 age- and gender-matched controls. The odds ratios (ORs) for PD risk for ever smokers versus never smokers were 0.27 (95% CI: 0.13-0.58) for men of genotype G, and 1.26 (0.60-2.63) for men of genotype A (interaction chi2 = 8.14, P = 0.004). In contrast, for women, the OR for ever smokers versus never smokers were 0.62 (95% CI: 0.25-1.34) and 0.64 (95% CI: 0.18-2.21) for women of genotype GG/GA and AA, respectively (interaction chi2 = 0.001, P = 0.975). No interactions were detected between smoking and either MAO-A EcoRV or DRD2 Taq1B genotypes. These results suggest that a strong gender difference exists with respect to the modifying effect of MAO-B genotype on the smoking association with PD.

An exceptional family with three consecutive generations affected by Wilson disease.

Wilson disease (WD) is a disorder of copper transport that can cause hepatic and neuropsychiatric symptoms. Because of its broad spectrum of clinical manifestations that can present in almost any decade of life, a high degree of clinical suspicion is needed for diagnosis. We present an exceptional family with three consecutive generations affected by WD. Autosomal recessive disorders are not typically present in consecutive generations, but this can occur, particularly when carrier frequencies are as high as in WD. This point is of critical importance in counseling families affected by WD. This case also highlights the importance of genetic testing in confirming the diagnosis of WD, particularly when there is a positive family history. To our knowledge, this is the first report of WD in three consecutive generations.

Novel mutations in ataxia telangiectasia and AOA2 associated with prolonged survival.

Ataxia telangiectasia (AT) and ataxia oculomotor apraxia type 2 (AOA2) are autosomal recessive ataxias caused by mutations in genes involved in maintaining DNA integrity. Lifespan in AT is greatly shortened (20s-30s) due to increased susceptibility to malignancies (leukemia/lymphoma). Lifespan in AOA2 is uncertain. We describe a woman with variant AT with two novel mutations in ATM (IVS14+2T>G and 5825C>T, p.A1942V) who died at age 48 with pancreatic adenocarcinoma. Her mutations are associated with an unusually long life for AT and with a cancer rarely associated with that disease. We also describe two siblings with AOA2, heterozygous for two novel mutations in senataxin (3 bp deletion c.343-345 and 1398T>G, p.I466M) who have survived into their 70s, allowing us to characterize the longitudinal course of AOA2. In contrast to AT, we show that persons with AOA2 can experience a prolonged lifespan with considerable motor disability.

Genotype and age at Parkinson disease diagnosis.

Parkinson disease (PD) is a degenerative movement disorder that results from the destruction of dopaminergic neurons in the midbrain substantia nigra. Both genetic and environmental factors contribute to PD risk, and likely to age at diagnosis. Among 258 newly diagnosed non-Hispanic Caucasian cases from Group Health Cooperative in western Washington State, we assessed whether diagnosis age was associated with 1,327 single nucleotide polymorphisms in genes related to central nervous system function, oxidative stress, inflammation or metal transport. We conducted linear regression to assess the age difference per variant allele while adjusting for sex and smoking. Of the polymorphisms associated with PD diagnosis age (ptrend<0.05), three demonstrated similar associations among 64 PD cases from the University of Washington Neurology Clinic, were not similarly associated (pinteraction<0.05) with age in general among 436 unrelated non-Hispanic Caucasian controls from the source population, and were predicted to be functional according to a public National Institute of Environmental Health Sciences polymorphism database. The most robust association was for rs10889162, a polymorphism in a predicted transcription factor binding site -582 bp from CYP2J2 arachidonic acid epoxygenase. Each variant allele was associated with 5.04 years older diagnosis age (95% confidence interval 2.28-7.80, p=0.0003). This association did not vary by sex or smoking history. Polymorphisms in predicted microRNA binding sites in GSTM5 and SLC11A2 were also associated with >2-year differences in diagnosis age. These results await confirmation in other series of incident cases, but suggest that selected genes and environmental exposures may influence PD diagnosis age.