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1.  A Rating Scale for the Functional Assessment of Patients with Familial Dysautonomia (Riley Day Syndrome) 
The Journal of pediatrics  2012;161(6):1160-1165.
Objective
To develop a reliable rating scale to assess functional capacity in children with familial dysautonomia, evaluate changes over time and determine whether severity within a particular functional category at a young age affected survival.
Study design
Ten functional categories were retrospectively assessed in 123 patients with familial dysautonomia at age 7 years ± 6 months. Each of the ten Functional Severity Scale (FuSS) categories (motor development, cognitive ability, psychological status, expressive speech, balance, oral coordination, frequency of dysautonomic crisis, respiratory, cardiovascular and nutritional status) was scored from 1 (worst or severely affected) to 5 (best or no impairment). Changes over time were analyzed further in 22 of the 123 patients who were also available at ages 17 and 27 years.
Results
Severely impaired cardiovascular function and high frequency of dysautonomic crisis negatively affected survival (p<0.005 and p<0.001, respectively). In the 22 individuals followed up to age 27 years, psychological status significantly worsened (p=0.01), and expressive speech improved (p=0.045). From age 17 to 27 years, balance worsened markedly (p =0.048).
Conclusion
The FuSS scale is a reliable tool to measure functional capacity in patients with familial dysautonomia. The scale may prove useful in providing prognosis and as a complementary endpoint in clinical trials.
doi:10.1016/j.jpeds.2012.05.038
PMCID: PMC3534733  PMID: 22727867
disease progression; functional health status; scoring system; survival rate
2.  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.
doi:10.1038/jhh.2011.107
PMCID: PMC3318957  PMID: 22129610
hypertension; renal failure; blood pressure instability; familial dysautonomia; afferent baroreflex failure
3.  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.
doi:10.1093/brain/awr168
PMCID: PMC3212710  PMID: 22075519
congenital insensitivity to pain; familial dysautonomia; HSAN; microneurography; muscle spindles; peripheral nerve; Riley–Day syndrome
4.  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.
doi:10.1203/PDR.0b013e31822e1825
PMCID: PMC3189334  PMID: 21775922
5.  Afferent baroreflex failure in familial dysautonomia 
Neurology  2010;75(21):1904-1911.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
GLOSSARY
= familial dysautonomia;
= forearm vascular resistance;
= pure autonomic failure.
doi:10.1212/WNL.0b013e3181feb283
PMCID: PMC2995385  PMID: 21098405
6.  Guidelines for the diagnosis and management of syncope (version 2009) 
Moya, Angel | Sutton, Richard | Ammirati, Fabrizio | Blanc, Jean-Jacques | Brignole, Michele | Dahm, Johannes B. | Deharo, Jean-Claude | Gajek, Jacek | Gjesdal, Knut | Krahn, Andrew | Massin, Martial | Pepi, Mauro | Pezawas, Thomas | Granell, Ricardo Ruiz | Sarasin, Francois | Ungar, Andrea | van Dijk, J. Gert | Walma, Edmond P. | Wieling, Wouter | Abe, Haruhiko | Benditt, David G. | Decker, Wyatt W. | Grubb, Blair P. | Kaufmann, Horacio | Morillo, Carlos | Olshansky, Brian | Parry, Steve W. | Sheldon, Robert | Shen, Win K. | Vahanian, Alec | Auricchio, Angelo | Bax, Jeroen | Ceconi, Claudio | Dean, Veronica | Filippatos, Gerasimos | Funck-Brentano, Christian | Hobbs, Richard | Kearney, Peter | McDonagh, Theresa | McGregor, Keith | Popescu, Bogdan A. | Reiner, Zeljko | Sechtem, Udo | Sirnes, Per Anton | Tendera, Michal | Vardas, Panos | Widimsky, Petr | Auricchio, Angelo | Acarturk, Esmeray | Andreotti, Felicita | Asteggiano, Riccardo | Bauersfeld, Urs | Bellou, Abdelouahab | Benetos, Athanase | Brandt, Johan | Chung, Mina K. | Cortelli, Pietro | Da Costa, Antoine | Extramiana, Fabrice | Ferro, José | Gorenek, Bulent | Hedman, Antti | Hirsch, Rafael | Kaliska, Gabriela | Kenny, Rose Anne | Kjeldsen, Keld Per | Lampert, Rachel | Mølgard, Henning | Paju, Rain | Puodziukynas, Aras | Raviele, Antonio | Roman, Pilar | Scherer, Martin | Schondorf, Ronald | Sicari, Rosa | Vanbrabant, Peter | Wolpert, Christian | Zamorano, Jose Luis
European Heart Journal  2009;30(21):2631-2671.
doi:10.1093/eurheartj/ehp298
PMCID: PMC3295536  PMID: 19713422

Results 1-6 (6)