H S A N T Y P E 3 R I L E Y D A Y S Y N D R O M E

B A T E L B A R A L U M A . M DT H E E D M O N D A N D L I L Y S A F R A C H I L D R E N ’S

H O S P I T A LS H E B A T E L H A S O M E R

Familial dysautonomia

The most common Hereditary Sensory and Autonomic Neuropathy.

All forms of HSANs have absent axon-reflex flare responses to intradermal application of histamine

Do not generate sensations of pain or temperature

Average survival is 30-35 years, main cause sudden death and respiratory insufficiency.

genetics

Ashkenazi Jewish descent. Carrier frequency 1:32, and 1:18 in polish.

It is caused by a single point mutation on chromosome 9q31 that affects gene IKBKAP, responsible for the production of IB kinase complex-associated protein.

1994 mapped on the 9q with enough DNA markers for prenatal screening and In 2001 sequence gene discovered with the single mutation (99.5%).

Since 2009 in the prenatal screening in Israel.

Mutation in intron 20, that weakens the splice site, with alternating splicing ----skipping of exon 20 and reduction of the protein expression -IKAP.

Tissue specific-

IKAP –subunit of elongator complex for RNA polymerase in nucleus

5 cardinal diagnosis criteria

absence of overflow emotional tears

absent lingual fungiform

depressed patellar reflexes

lack of an axon flare following intradermal histamine

Ashkenazi Jewish extraction

Not a criteria- intermediate phalange shorter then distal

Most common symptoms

Ocular: decreased tears 99% Corneal analgesia Optic atrophy Gastro: Dysphagia 60% Esophageal and gastric dysmotility 60% Gastroesophageal reflux 67% Vomiting crises 45% Pulmonary: Aspirations Insensitivity to hypoxia Restrictive lung disease Ortho: Spinal curvature 85% Asceptic necrosis 15% Vasomotor: Postural Hypotension 99% Blotching 99% Excessive sweating 99% Hypertensive crises >60% Neuro: Decreased deep tendon reflexes 95% Decreased pain and temperature sensation Decreased vibration (after 13years) Progressive ataxia

Autonomic crisis

Recurrent episodes with uncontrolled release of catecholamines from sympathetic nerve terminals at times of stress.

Treated with benzodiazepine, clonidine ,first generation antihistamine (atarax, phenergan) and PPI.

gastro

Oropharyngeal incoordination- In the pharyngeal phase: Delayed relaxation of cricopharingeus.

Esophageal motility disturbances and improper relaxation of lower esophageal sphincter.

GI reflux- gastrostomy+funduplication are recommended early in life.

Gastric ulcers- signs of active bleeding obscure because of blood pressure labile.

intelligence

Most affected individuals are of normal intelligence.

In one study, 28% of FD patients had less than average intelligence

lungs

Aspiration pneumonia frequent mostly infancy and childhood with major damage. CT on 33 patients showed 27% bronchiectasis. Most common bronchial and pleural thickening, uneven ventilation and airtrapping. Inflammation causes obstructive pattern.

Restrictive- kyphscoliosis, incoordinate breathing not having MS, spine surgery that causes chest rigidity.

kidney

35% have elevated creatinine and after age of 25, 20% require dialysis.

Maybe IKAP important for renal development, and in FD more vulnerable to hypertensive exposure.

Treatment : carbidopa reduces variability

3 mouse models:

Dragastis(homologous recombination of the mouse IKBKAP gene- lack of expression or lacking exon 20: develop- mental delays, cardiovascular and brain malformations)

Salgenhaght (BAC: bacterial artificial chromosome)

Gil Ast(knock in human gene- exon 20 and 2 flanking introns) – non of phenotypical FD.

PFT’s in FD

limited to a few patients demonstrating air flow limitation(obstruction) and associated lung restriction with reduction in diffusion capacity.

No description of response to bronchodilators !!!!

Dysautonomia is by definition characterized with abnormal sympathetic and parasympathetic system

Is the use of sympathomimetics and parasympatholytics appropriate? Safe? Are the β2 receptors or the muscarinic receptors are functional?

methods

randomized double-blind placebo controlled crossover study

patients were randomized to receive albuterol, ipratropium bromide or placebo (0.9% sodium chloride) via nebulizer.

beat-to-beat blood pressure, heart rate and cardiac impedance plethysmography were measured in the seated position over 5-minutes

Baseline spirometry and impulse oscillometry (IOS) were performed three times

methods

30 minutes after nebulization respiratory function tests were repeated and autonomic measurements were recorded for 5-minutes.

Patients returned within one-week and were crossed over to receive the next intervention.

each subject received albuterol, ipratropium and placebo in random order sequence

Cardiac Impedance plethysmography

Impedance plethysmography is a method of determining changing tissue volumes in the body, based on the measurement of electric impedance at the body surface

results

10 out of 12 patients performed all 3 sessions

Mean age was 29±11.8 (16-55) years. M/F-5/7.

albuterol and Ipratropium showed an increment of FEV1≥10% in 5/10 patients (50%), and both medications were effective in improving FEV1 when compared with Placebo (p

Figure 1: Change in FEV1 post inhalation in all participants. Improvement with both albuterol and ipratropium bromide is evident in most patients.

Figure 2: Change in % of the Resistance at 5 Hz. In most patients reduction of resistance is evident post inhalation with both albuterol and ipratropium bromide.

No significant change in mean blood pressure (mmHg) post inhalation with both albuterol and ipratropium, as compared with placebo (saline).

FD patients demonstrate a positive response to both beta-2-agonists and anticholinergic inhaled drugs

Can it be that the positive response to anticholinergic is a result of recurrent aspiration with denudation of the mucosa and the vagal endings are more exposed and irritated? Can we assume that in aspiration there is preference for anticholinergic in general?

Summary

Summary

All cardiovascular measurements were stable , with no change in variability compared with baseline measurements. Even when the drug reached pick effect pharmaco-dynamically.

Conclusions

More studies are required to establish the effects of the inhaled drugs, with ABG’s to evaluate improvement in hypoxia? Hypercarbia?

The addative effect of both drugs should be also evaluated , for safety as well as for synergic effect.

Measurements of beta agonists in the blood

Conclusions

Most FD patients demonstrate obstructive lung disease as demonstrated with a positive response to bronchodilators in PFT’s

Both bronchodilators are safe and well tolerated

No response to bronchodilators is seen in some patients receptor’s activity, that theoretically can be different between patients according to phenotype severity

Both spirometry and IOS are valuable tools for the evaluation of airway obstruction in FD