Faculty Bibliography

Familial dysautonomia (FD) is caused by a splicing error in the IKBKAP gene that encodes human Elongator protein-1 (ELP-1). In these patients, exon 20 is frequently skipped duringmRNA splicing, but cells retain the ability to produce a lowlevel of normal (wild-type) IKBKAPmRNAand normal protein. Phosphatidylserine (PS, Sharp-thought), an acidic phospholipid, has been shown to raise elongator protein-1 levels by increasing IKBKAPtranscription in fibroblast cell-lines derived fromFD patients and, more recently, in a mouse model of FD. Given that PS is available over the counter, weconducted a study to determinewhether PS raises IKBKAP gene expression in patients with FD. We enrolled 7 patients with FD, 16-23 years old, in an open-label titration protocol. Patients were examined at baseline (visit 1), after 2 months of taking 300 mg/day (visit 2) and again after 2 months of taking 600 mg/day of PS(visit 3).Bloodwas taken at each visit. Sampleswere de-identified and investigators blinded to the sample identity. Blood was treated with Tri- Reagent, and RNA extracted according to manufacturers specifications. Quantitative polymerase chain reaction (qPCR) was performed to measure the level of normal IKBKAPmRNA. PSwas well tolerated and there were no adverse events or unexpected laboratory abnormalities. After 2 months of taking 300 mg of PS per day, there was a trend for IKBKAP mRNA levels to increase. After 2 months of 600 mg of PS per day, IKBKAPmRNAexpression increased between 2 and 8 fold in all but one patient (p<0.01). Our results indicate that PS safely raises wild-type IKBKAP mRNA levels in blood from patients with FD, opening an exciting potential therapeutic path for treatment. Clinical trials to determine whether restoring Elongator protein 1 levels impacts the phenotype are underway

Multiple system atrophy (MSA) is a fatal, relentlessly progressive, adult-onset neurodegenerative disorder that affects at least 4 per 100,000 people in the US. MSA is characterized clinically by a variable combination of parkinsonism, cerebellar ataxia and autonomic abnormalities and pathologically by cytoplasmic inclusions of fibrillized asynuclein protein aggregates in oligodendroglia and neurons. There is no effective treatment for MSA and death occurs, on average, 8 years after onset of symptoms. The cause of MSA is unknown but abnormal metabolism and aggregation of alpha-synuclein has emerged as the leading cause of neurodegeneration. Although the mechanisms that lead to synuclein aggregation are unknown, there is evidence to support roles for oxidative stress due to mitochondrial dysfunction and microglial activation. Recent experimental data suggest that alpha-synuclein can be absorbed by oligodendroglia and neurons from the extracellular space and that cell-to-cell transmission of abnormal alpha-synuclein in a prionlike manner may explain the progressive nature of MSA. Potential therapeutic strategies targeting each of the proposed mechanisms of asynuclein aggregation and propagation will be reviewed

In Parkinson disease (PD), symptoms and signs of autonomic failure occur commonly, especially in cardiovascular, gastrointestinal, and genitourinary domains. Most patients with PD have neuroimaging evidence of cardiac sympathetic denervation. In PD, orthostatic hypertension (OH) can be an early finding and is associated with extracardiac noradrenergic denervation and reduced baroreflex-cardiovagal and sympathoneural responses. Recognition of autonomic impairment is important because symptomatic treatment is frequently effective.

The maintenance of blood pressure in the upright position requires intact autonomic cardiovascular reflexes. Diseases that affect the sympathetic innervation of the cardiovascular system result in a sustained fall in blood pressure upon standing (i.e., neurogenic orthostatic hypotension) that can impair the blood supply to the brain and other organs and cause considerable morbidity and mortality. Here we review treatment options for neurogenic orthostatic hypotension and include an algorithm for its management that emphasizes the importance of non-pharmacologic measures and provides guidance on pharmacologic treatment options.

Takotsubo cardiomyopathy is an acute reversible cardiac dysfunction syndrome associated with high circulating catecholamine levels. Our objective was to investigate whether abnormal cardiovascular control might play a role in the pathophysiology. We studied autonomic cardiovascular reflexes in 10 women who had takotsubo (33+/-7 months after being hospitalized) and 10 age/BMI matched healthy women. In the women with takotsubo, indices of vagal modulation of heart rate induced by respiration were uniformly reduced (expiratory:inspiratory ratio: p<0.01, pnn50%: p<0.02, rMSSD: p<0.03). Cognitive (stroop test: p<0.03) and emotional arousal (event recall: p<0.05) produced exaggerated pressor responses, without detectable ECG changes. Pressor responses to hemodynamic stimuli were also amplified (Valsalva SBP overshoot: p<0.05). Takotsubo women had increased BP variability in the short-term (St. Dev. SBP: p<0.01). Ambulatory recordings captured an exaggerated morning surge in SBP after awakening from sleep (p<0.05). Cardiovagal baroreflex gain was significantly lower in the takotsubo women (sequence analysis: p<0.01, regression method: p<0.001, transfer function gain: p<0.001). Women with takotsubo have heightened sympathetic responsiveness, labile BP and reduced vagal modulation of the heart. This shift in sympathovagal balance could play a role in the pathophysiology

BACKGROUND: Hereditary sensory and autonomic neuropathy type III features marked ataxic gait that progressively worsens over time. We assessed whether proprioceptive disturbances can explain the ataxia. METHODS: Proprioception at the knee joint was assessed using passive joint angle matching in 18 patients and 14 age-matched controls; 5 patients with cerebellar ataxia were also studied. Ataxia was quantified using the Brief Ataxia Rating Score, which ranged from 7 to 26 of 30. RESULTS: Neuropathy patients performed poorly in judging joint position: mean absolute error was 8.7 degrees +/- 1.0 degrees , and the range was very wide (2.8 degrees -18.1 degrees ); conversely, absolute error was only 2.7 degrees +/- 0.3 degrees (1.6 degrees -5.5 degrees ) in the controls and 3.0 degrees +/- 0.2 degrees (2.1 degrees -3.4 degrees ) in the cerebellar patients. This error was positively correlated to the degree of ataxia in the neuropathy patients but not the cerebellar patients. CONCLUSIONS: These results suggest that poor proprioceptive acuity at the knee joint is a major contributor to the ataxic gait associated with hereditary sensory and autonomic neuropathy type III.

OBJECTIVE: To compare active standing vs. passive head up tilt (HUT) in the diagnosis of orthostatic hypotension (OH) in patients with Parkinson disease (PD). BACKGROUND: Although both methods are used, it is not known whether active standing or HUT are better suited for the diagnosis of OH in patients with PD. DESIGN/METHODS: We compared the frequency of OH (i.e., fall in 20/10 mmHg within 3 minutes) when assessed by HUT vs. active standing in 233 patients with PD. 116 patients (73 men and 43 women) underwent a 60 degree HUT and 117 patients (62 men and 53 women) underwent an active standing procedure. Blood pressure and heart rate were measured before and after 3 minutes in the upright position. RESULTS: The prevalence of OH was 70% in those undergoing HUT and 41% in those undergoing active standing (p<0.001). However, patients undergoing HUT were significantly older (72.1 years vs. 61.2 years, p<0.001) and had higher systolic blood pressure while supine (151 vs. 134 mmHg, p<0.001). Prevalence of OH by age showed that the 40-50 yrs old group (n:15) had 20% prevalence of OH with HUT vs. 40% with active standing (NS); in the 50-60 yrs old group (n:38), 33% had OH with HUT vs. 47% with active standing (NS), in the 60-70 yr old group (n:67), 78% had OH with HUT vs. 43% with active standing (p<0.004), and in the 70-80 yrs old group (n:85), 60% had OH with HUT and 36% with active standing (p<0.04). CONCLUSIONS: In younger patients with PD active standing and HUT showed similar prevalence of OH. However, among PD patients 60 years and older the prevalence of OH was significantly higher with HUT than with active standing. These findings have practical implication for diagnosis and clinical management

OBJECTIVE: To determine if carbidopa, a dopa-decarboxylase inhibitor that blocks the formation of dopamine outside the brain, is an effective antiemetic in patients with familial dysautonomia (FD). BACKGROUND: Patients with FD, an hereditary neuropathy that affects the development of sensory neurons of the baroreflex, are unable to restrain the release of catecholamines from sympathetic nerve terminals at times of stress. Recurrent attacks of nausea, retching and vomiting, associated with high levels of circulating dopamine are a disabling feature of the disease for which there is no effective treatment. DESIGN/METHODS: We enrolled 12 patients with FD in an open-label titration and treatment study to assess the safety of carbidopa, an inhibitor of the enzyme dopa decarboxylase that does not cross the blood brain barrier. We then conducted a randomized, double-blind, placebo-controlled, crossover study to evaluate its antiemetic efficacy. RESULTS: All patients experienced severe cyclical nausea and uncontrollable retching that was refractory to standard treatments. Carbidopa at an average daily dose of 480 mg (range 325 to 600 mg/day) was well tolerated. In the double-blind phase, patients experienced significantly less nausea and retching while on carbidopa than on placebo (p<0.03 and p<0.02. respectively). Twenty-four hour urinary dopamine excretion was significantly lower while on carbidopa (147+/-32 ug/g crt) than while on placebo (222+/-41 ug/g crt, p<0.05). CONCLUSIONS: Carbidopa appears to be a safe and effective antiemetic in patients with FD likely by reducing the formation of dopamine outside the brain. Larger trials are warranted

OBJECTIVE: The purpose of this study was to determine whether carbidopa (Lodosyn), an inhibitor of dopa-decarboxylase that blocks the synthesis of dopamine outside the brain, is an effective antiemetic in patients with familial dysautonomia (FD) and hyperdopaminergic nausea/retching/vomiting attacks. METHODS: We enrolled 12 patients with FD in an open-label titration and treatment study to assess the safety of carbidopa. We then conducted a randomized, double-blind, placebo-controlled, crossover study to evaluate its antiemetic efficacy. RESULTS: Previous fundoplication surgery in each patient studied prevented vomiting, but all of the subjects experienced severe cyclical nausea and uncontrollable retching that was refractory to standard treatments. Carbidopa at an average daily dose of 480 mg (range 325-600 mg/day) was well tolerated. In the double-blind phase, patients experienced significantly less nausea and retching while on carbidopa than on placebo (p < 0.03 and p < 0.02, respectively). Twenty-four-hour urinary dopamine excretion was significantly lower while on carbidopa (147 +/- 32 microg/gCr) than while on placebo (222 +/- 41microg/gCr, p < 0.05). CONCLUSIONS: Carbidopa is a safe and effective antiemetic in patients with FD, likely by reducing the formation of dopamine outside the brain. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that carbidopa is effective in reducing nausea/retching/vomiting in patients with FD.

Familial dysautonomia (Riley-Day syndrome) is an hereditary sensory and autonomic neuropathy (HSAN type III), expressed at birth, that is associated with reduced pain and temperature sensibilities and absent baroreflexes, causing orthostatic hypotension as well as labile blood pressure that increases markedly during emotional excitement. Given the apparent absence of functional baroreceptor afferents, we tested the hypothesis that the normal cardiac-locked bursts of muscle sympathetic nerve activity (MSNA) are absent in patients with familial dysautonomia. Tungsten microelectrodes were inserted percutaneously into muscle or cutaneous fascicles of the common peroneal nerve in 12 patients with familial dysautonomia. Spontaneous bursts of MSNA were absent in all patients, but in five patients we found evidence of tonically firing sympathetic neurones, with no cardiac rhythmicity, that increased their spontaneous discharge during emotional arousal but not during a manoeuvre that unloads the baroreceptors. Conversely, skin sympathetic nerve activity (SSNA), recorded in four patients, appeared normal. We conclude that the loss of phasic bursts of MSNA and the loss of baroreflex modulation of muscle vasoconstrictor drive contributes to the poor control of blood pressure in familial dysautonomia, and that the increase in tonic firing of muscle vasoconstrictor neurones contributes to the increase in blood pressure during emotional excitement.