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1.  Cerebellar and parkinsonian phenotypes in multiple system atrophy: Similarities, differences and survival 
Multiple system atrophy (MSA) is a neurodegenerative disease with two motor phenotypes: parkinsonian (MSA-P) and cerebellar (MSA-C). To elucidate whether in addition to the motor abnormalities there are other significant differences between these phenotypes we performed a retrospective review of 100 patients (61 males, 39 females) with a diagnosis of possible (12%), or probable (88%). Four patients eventually had postmortem confirmation (i.e., definite MSA). Sixty percent were classified as having MSAP and 40% as MSA-C. MSA-C and MSA-P patients had similar male prevalence (60%), age of onset (56±9 years), and frequency of OH (69%). Brain MRI abnormalities were more frequent in MSA-C patients (p<0.001). Mean survival was 8±3 years for MSA-C and 9±4 years for MSA-P patients (p=0.22). Disease onset before 55 years predicted longer survival in both phenotypes. Initial autonomic involvement did not influence survival. We conclude that patients with both motor phenotypes have mostly similar survivals and demographic distributions. The differences here identified could help counseling of patients with MSA.
PMCID: PMC4134009  PMID: 24337696
MSA; MSA-P; MSA-C; parkinsonism; cerebellar; autonomic; MRI
2.  Disturbances in affective touch in hereditary sensory & autonomic neuropathy type III 
Hereditary sensory and autonomic neuropathy type III (HSAN III, Riley–Day syndrome, Familial Dysautomia) is characterised by elevated thermal thresholds and an indifference to pain. Using microelectrode recordings we recently showed that these patients possess no functional stretch-sensitive mechanoreceptors in their muscles (muscle spindles), a feature that may explain their lack of stretch reflexes and ataxic gait, yet patients have apparently normal low-threshold cutaneous mechanoreceptors. The density of C-fibres in the skin is markedly reduced in patients with HSAN III, but it is not known whether the C-tactile afferents, a distinct type of low-threshold C fibre present in hairy skin that is sensitive to gentle stroking and has been implicated in the coding of pleasant touch are specifically affected in HSAN III patients. We addressed the relationship between C-tactile afferent function and pleasant touch perception in 15 patients with HSAN III and 15 age-matched control subjects. A soft make-up brush was used to apply stroking stimuli to the forearm and lateral aspect of the leg at five velocities: 0.3, 1, 3, 10 and 30 cm/s. As demonstrated previously, the control subjects rated the slowest and highest velocities as less pleasant than those applied at 1–10 cm/s, which fits with the optimal velocities for exciting C-tactile afferents. Conversely, for the patients, ratings of pleasantness did not fit the profile for C-tactile afferents. Patients either rated the higher velocities as more pleasant than the slow velocities, with the slowest velocities being rated unpleasant, or rated all velocities equally pleasant. We interpret this to reflect absent or reduced C-tactile afferent density in the skin of patients with HSAN III, who are likely using tactile cues (i.e. myelinated afferents) to rate pleasantness of stroking or are attributing pleasantness to this type of stimulus irrespective of velocity.
•C-tactile afferents in hairy skin are believed to mediate affective touch.•They are sensitive to slow brushing stimuli, which are perceived as pleasant.•It is not known whether C-tactile afferents are affected in HSAN III.•Ratings of pleasantness were reduced in 15 HSAN III patients compared to controls.•We suggest that the density of C-tactile afferents is reduced in HSAN III.
PMCID: PMC4078239  PMID: 24726998
Affective touch; CT afferents; Pleasant touch; Tactile sensation
Hereditary sensory and autonomic neuropathy type III features a marked ataxic gait that progressively worsens over time. We assessed whether proprioceptive disturbances can explain the ataxia. 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 26/30. Neuropathy patients performed poorly in judging joint position: mean absolute error was 8.7±1.0° and the range was very wide (2.8–18.1°); conversely, absolute error was only 2.7±0.3° (1.6–5.5°) in the controls and 3.0±0.2° (2.1–3.4°) in the cerebellar patients. This error was positively correlated to the degree of ataxia in the neuropathy patients but not the cerebellar patients, suggesting 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.
PMCID: PMC3694996  PMID: 23681701
congenital insensitivity to pain; familial dysautonomia; joint sense; hereditary sensory & autonomic neuropathy; muscle spindles; proprioception; Riley-Day syndrome
4.  Hyperdopaminergic crises in familial dysautonomia 
Neurology  2013;80(17):1611-1617.
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.
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.
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 µg/gCr) than while on placebo (222 ± 41µg/gCr, p < 0.05).
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.
PMCID: PMC3662326  PMID: 23553478
5.  Developmental Abnormalities, Blood Pressure Variability and Renal Disease In Riley Day Syndrome 
Journal of human hypertension  2011;27(1):51-55.
Riley Day syndrome, commonly referred to as familial dysautonomia (FD), is a genetic disease with extremely labile blood pressure due to baroreflex deafferenation. Chronic renal disease is very frequent in these patients and was attributed to recurrent arterial hypotension and renal hypoperfusion. Aggressive treatment of hypotension, however, has not reduced its prevalence.
We evaluated the frequency of kidney malformations as well as the impact of hypertension, hypotension and blood pressure variability on the severity of renal impairment. We also investigated the effect of fludrocortisone treatment on the progression of renal disease.
Patients with FD appeared to have an increased incidence of hydronephrosis/reflux and patterning defects. Patients younger than 4 years old had hypertension and normal eGFR. Patients with more severe hypertension and greater variability in their blood pressure had worse renal function (both, p<0.01). In contrast, there was no relationship between eGFR and the lowest blood pressure recorded during upright tilt. The progression of renal disease was faster in patients receiving fludrocortisone (p<0.02).
Hypertension precedes kidney disease in these patients. Moreover, increased blood pressure variability as well as mineralocorticoid treatment accelerate the progression of renal disease. No association was found between hypotension and renal disease in patients with FD.
PMCID: PMC3318957  PMID: 22129610
hypertension; renal failure; blood pressure instability; familial dysautonomia; afferent baroreflex failure
6.  Can loss of muscle spindle afferents explain the ataxic gait in Riley–Day syndrome? 
Brain  2011;134(11):3198-3208.
The Riley–Day syndrome is the most common of the hereditary sensory and autonomic neuropathies (Type III). Among the well-recognized clinical features are reduced pain and temperature sensation, absent deep tendon reflexes and a progressively ataxic gait. To explain the latter we tested the hypothesis that muscle spindles, or their afferents, are absent in hereditary sensory and autonomic neuropathy III by attempting to record from muscle spindle afferents from a nerve supplying the leg in 10 patients. For comparison we also recorded muscle spindles from 15 healthy subjects and from two patients with hereditary sensory and autonomic neuropathy IV, who have profound sensory disturbances but no ataxia. Tungsten microelectrodes were inserted percutaneously into fascicles of the common peroneal nerve at the fibular head. Intraneural stimulation within muscle fascicles evoked twitches at normal stimulus currents (10–30 µA), and deep pain (which often referred) at high intensities (1 mA). Microneurographic recordings from muscle fascicles revealed a complete absence of spontaneously active muscle spindles in patients with hereditary sensory and autonomic neuropathy III; moreover, responses to passive muscle stretch could not be observed. Conversely, muscle spindles appeared normal in patients with hereditary sensory and autonomic neuropathy IV, with mean firing rates of spontaneously active endings being similar to those recorded from healthy controls. Intraneural stimulation within cutaneous fascicles evoked paraesthesiae in the fascicular innervation territory at normal stimulus intensities, but cutaneous pain was never reported during high-intensity stimulation in any of the patients. Microneurographic recordings from cutaneous fascicles revealed the presence of normal large-diameter cutaneous mechanoreceptors in hereditary sensory and autonomic neuropathy III. Our results suggest that the complete absence of functional muscle spindles in these patients explains their loss of deep tendon reflexes. Moreover, we suggest that their ataxic gait is sensory in origin, due to the loss of functional muscle spindles and hence a compromised sensorimotor control of locomotion.
PMCID: PMC3212710  PMID: 22075519
congenital insensitivity to pain; familial dysautonomia; HSAN; microneurography; muscle spindles; peripheral nerve; Riley–Day syndrome
7.  Kinetin improves IKBKAP mRNA splicing in patients with familial dysautonomia 
Pediatric research  2011;70(5):480-483.
Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-κ-B kinase complex associated protein/ elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase wild-type IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine if oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation. Subjects received 23.5 mg/Kg/day for 28 days. An increase in wild-type IKBKAP mRNA expression in leukocytes was noted after eight days in six of eight individuals; after 28 days the mean increase as compared to baseline was significant (p=0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients, but also that effect appears to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine if kinetin will prove therapeutic in FD patients.
PMCID: PMC3189334  PMID: 21775922
8.  Afferent baroreflex failure in familial dysautonomia 
Neurology  2010;75(21):1904-1911.
Familial dysautonomia (FD) is due to a genetic deficiency of the protein IKAP, which affects development of peripheral neurons. Patients with FD display complex abnormalities of the baroreflex of unknown cause.
To test the hypothesis that the autonomic phenotype of FD is due to selective impairment of afferent baroreceptor input, we examined the autonomic and neuroendocrine responses triggered by stimuli that either engage (postural changes) or bypass (cognitive/emotional) afferent baroreflex pathways in 50 patients with FD and compared them to those of normal subjects and to those of patients with pure autonomic failure (PAF), a disorder with selective impairment of efferent autonomic neurons.
During upright tilt, in patients with FD and in patients with PAF blood pressure fell markedly but the heart rate increased in PAF and decreased in FD. Plasma norepinephrine levels failed to increase in both groups. Vasopressin levels increased appropriately in patients with PAF but failed to increase in patients with FD. Head-down tilt increased blood pressure in both groups but increased heart rate only in patients with FD. Mental stress evoked a marked increase in blood pressure and heart rate in patients with FD but little change in those with PAF.
The failure to modulate sympathetic activity and to release vasopressin by baroreflex-mediated stimuli together with marked sympathetic activation during cognitive tasks indicate selective failure of baroreceptor afference. These findings indicate that IKAP is critical for the development of afferent baroreflex pathways and has therapeutic implications in the management of these patients.
= familial dysautonomia;
= forearm vascular resistance;
= pure autonomic failure.
PMCID: PMC2995385  PMID: 21098405

Results 1-8 (8)