A Call to Action: The Role of Healthcare Providers in Reducing the Burden Associated with Neurogenic Orthostatic Hypotension.

Neurogenic orthostatic hypotension (nOH) is a sustained fall in blood pressure upon standing that frequently affects patients with neurodegenerative diseases (e.g., Parkinson disease) and manifests with symptoms such as lightheadedness and dizziness upon standing. nOH can severely affect patients by increasing the risk of falls and injuries and by decreasing functionality, independence, and quality of life. However, the condition is often under-recognized because of many factors, including the nonspecific nature of the symptoms, patient comorbidities, and patients' reluctance to discuss their symptoms with their healthcare providers. Increased awareness of the burden of nOH and recognition of potential barriers to efficient diagnosis may lead to improved clinical outcomes and better quality of life for patients. To better understand the manifestations and real-life impact of living with nOH symptoms, perspectives from a patient with nOH and his caregiver (wife) are provided, along with key findings from a published survey of patients and caregivers on the burden of nOH. In addition, insights and advice on a practical approach for diagnosing, educating, and treating patients with nOH are outlined.

This article discusses what neurogenic orthostatic hypotension (nOH) is, its symptoms, and how patients and healthcare providers (HCPs) can work together to manage nOH symptoms. What is nOH? People with neurologic disorders, like Parkinson disease, may also have a separate condition called nOH. nOH occurs when blood pressure drops too much when standing up after sitting or lying down. What are the symptoms of nOH, and how can they affect people's lives? Most often, people with nOH report feeling lightheaded, faint, or dizzy when standing up. Other symptoms of nOH include pain in the shoulders and neck, trouble thinking clearly, tiredness, or blurry vision. The symptoms of nOH can cause falls and injuries. Because of nOH symptoms, people may be unable to do daily activities and may feel worried or anxious. What do patients and HCPs need to know when discussing nOH symptoms? A survey showed that patients may not talk about their nOH symptoms with their HCPs unless symptoms are severe, and that patients can find receiving a diagnosis of nOH challenging. Patients can track nOH symptoms in a daily journal to use in discussions with their HCPs. How can HCPs help patients with nOH? HCPs can ask patients with underlying neurologic disorders about symptoms that occur on standing and confirm a diagnosis of nOH by comparing the patient's blood pressures measured lying down and after standing up. HCPs can provide information about lifestyle changes and medications that are available to manage nOH symptoms.

A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.

IMPORTANCE: Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit. OBJECTIVE: To examine whether CoQ10 could slow disease progression in early PD. DESIGN, SETTING, AND PARTICIPANTS: A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation. INTERVENTIONS: The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E. MAIN OUTCOMES AND MEASURES: Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo. RESULTS: The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo). CONCLUSIONS AND RELEVANCE: Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00740714.

A family with Parkinson disease, essential tremor, bell palsy, and parkin mutations.

BACKGROUND: Mutations in the parkin gene cause autosomal recessive early-onset Parkinson disease (EOPD). The A265G variant in the HS1 binding protein 3 gene (HS1BP3) is common in essential tremor (ET). OBJECTIVE: To investigate the presence of mutations in the parkin gene and the A265G variant in the HS1BP3 gene in a Mexican family with EOPD, ET, and Bell palsy. DESIGN: Direct sequencing, semiquantitative polymerase chain reaction, and reverse transcription-polymerase chain reaction were performed in the 14 members of this family. SETTING: Mexican family. Patients Two patients with EOPD were analyzed. RESULTS: Compound heterozygous mutations (EX 3_6 del and EX 5 del) in the parkin gene were identified in 2 patients with EOPD, characterized by beneficial response to levodopa, relatively slow progression, and motor complications. Although heterozygous EX 3_6 del and homozygous EX 5 del mutations in the parkin gene have been previously described, to our knowledge, this is the first report of these mutations in compound heterozygotes. Seven heterozygous A265G variants in the HS1BP3 gene were found in this pedigree, but they did not cosegregate with ET, Parkinson disease, or Bell palsy, supporting the conclusion that this variant is not associated with ET. CONCLUSIONS: Compound heterozygous parkin mutations (EX 3_6 del and EX 5 del) caused EOPD in this family, but the A265G variant in the HS1BP3 gene, previously considered to be responsible for ET, was probably not pathogenically related to the ET in this family.

Genetic analysis of LRRK2 mutations in patients with Parkinson disease.

In addition to the G2019S mutation in the leucine-rich repeat kinase 2 gene (LRRK2), which is particularly frequent in patients of Ashkenazi Jewish and Northern African origin, three amino acid substitutions (R1441C, R1441G, and R1441H), all at the same residue (R1441), have been identified as important genetic causes of Parkinson disease (PD). To evaluate the frequency of R1441C/G/H and G2019S mutations in the LRRK2 gene in North American patients with PD and to explore genotype-phenotype correlations, we screened 496 PD patients from North America. One Hispanic female was heterozygous for the LRRK2 R1441G mutation, and six other cases including 2 non-Jewish/non-Hispanic whites, 3 Ashkenazi Jewish, and 1 Hispanic, were found to be heterozygous for the LRRK2 G2019S mutation. G2019S mutation in the LRRK2 gene is a common mutation associated with PD in a North American population, especially in Jewish PD patients (10.7%), while the R1441C/G/H mutation occurs at a relatively low frequency in North Americans except possibly in Hispanics for R1441G. All six G2019S carriers shared a common haplotype with that observed in Europeans and North Africans. The clinical features of all seven cases with LRRK2 mutation were quite broad and included early and late disease onset. These finding may provide new insights into the cause and diagnosis of PD and have implications for genetic counseling.

Heterogeneous phenotype in a family with compound heterozygous parkin gene mutations.

BACKGROUND: Mutations in the parkin gene (PRKN) cause autosomal recessive early-onset Parkinson disease (EOPD). OBJECTIVE: To investigate the presence of mutations in the PRKN gene in a white family with EOPD and the genotype-phenotype correlations. DESIGN: Twenty members belonging to 3 generations of the EOPD family with 4 affected subjects underwent genetic analysis. Direct genomic DNA sequencing, semiquantitative polymerase chain reaction, real-time quantitative polymerase chain reaction, and reverse-transcriptase polymerase chain reaction analyses were performed to identify the PRKN mutation. RESULTS: Compound heterozygous mutations (T240M and EX 5_6 del) in the PRKN gene were identified in 4 patients with early onset (at ages 30-38 years). Although heterozygous T240M and homozygous EX 5_6 del mutations in the PRKN gene have been previously described, this is, to our knowledge, the first report of these mutations in compound heterozygotes. The phenotype of patients was that of classic autosomal recessive EOPD characterized by beneficial response to levodopa, relatively slow progression, and motor complications. All heterozygous mutation carriers (T240M or EX 5_6 del) and a 56-year-old woman who was a compound heterozygous mutation carrier (T240M and EX 5_6 del) were free of any neurological symptoms. CONCLUSIONS: Compound heterozygous mutations (T240M and EX 5_6 del) in the PRKN gene were found to cause autosomal recessive EOPD in 4 members of a large white family. One additional member with the same mutation, who is more than 10 years older than the mean age at onset of the 4 affected individuals, had no clinical manifestation of the disease. This incomplete penetrance has implications for genetic counseling, and it suggests that complex gene-environment interactions may play a role in the pathogenesis of PRKN EOPD.