Clinical Autonomic Research

, Volume 18, Issue 3, pp 115–119 | Cite as

Cardiac sympathetic hypo-innervation in familial dysautonomia

  • David S. Goldstein
  • Basil Eldadah
  • Yehonatan Sharabi
  • Felicia B. Axelrod



Familial dysautonomia (FD) involves incomplete development of the sympathetic nervous system. Whether such loss extends to sympathetic innervation of the heart has been unknown. This study used 6-[18F]fluorodopamine neuroimaging to assess cardiac sympathetic innervation and function in FD.


Six adult FD patients underwent thoracic PET scanning for 30 minutes after i.v. 6-[18F]fluorodopamine injection, as did healthy volunteers without (N = 21) or with (N = 10) pre-treatment by desipramine, which interferes with neuronal uptake and thereby simulates effects of noradrenergic denervation. Effective rate constants for uptake and loss were calculated using a single compartment pharmacokinetic model.


FD patients had decreased uptake and accelerated loss of 6-[18F]fluorodopamine-derived radioactivity in the interventricular myocardial septum (P = 0.009, P = 0.05) and ventricular free wall (P = 0.007, P < 0.001), compared to untreated controls. Desipramine-treated subjects had decreased uptake but normal loss of 6-[18F]fluorodopamine-derived radioactivity.


FD involves cardiac noradrenergic hypo-innervation. Since accelerated loss of 6-[18F]fluorodopamine-derived radioactivity cannot be explained by decreased neuronal uptake alone, FD may also involve augmented NE loss from extant terminals.


familial dysautonomia fluorodopamine sympathetic nervous system positron emission tomography norepinephrine 



This research was supported by the Intramural Research Program of the NIH, National Institute of Neurological Disorders and Stroke.


  1. 1.
    Axelrod FB (2006) A world without pain or tears. Clin Auton Res 16:90–96PubMedCrossRefGoogle Scholar
  2. 2.
    Axelrod FB, Goldberg JD, Ye XY, Maayan C (2002) Survival in familial dysautonomia: impact of early intervention. J Pediatr 141:518–523PubMedCrossRefGoogle Scholar
  3. 3.
    Close P, Hawkes N, Cornez I, Creppe C, Lambert CA, Rogister B, Siebenlist U, Merville MP, Slaugenhaupt SA, Bours V, Svejstrup JQ, Chariot A (2006) Transcription impairment and cell migration defects in elongator-depleted cells: implication for familial dysautonomia. Mol Cell 22:521–531PubMedCrossRefGoogle Scholar
  4. 4.
    Freedman LS, Ebstein RP, Goldstein M, Axelrod FB, Dancis J (1975) Serum dopamine-beta-hydroxylase in familial dysautonomia. J Lab Clin Med 85:1008–1012PubMedGoogle Scholar
  5. 5.
    Glickstein JS, Axelrod FB, Friedman D (1999) Electrocardiographic repolarization abnormalities in familial dysautonomia: an indicator of cardiac autonomic dysfunction. Clin Auton Res 9:109–112PubMedCrossRefGoogle Scholar
  6. 6.
    Gold-von Simson G, Rutkowski M, Berlin D, Axelrod FB (2005) Pacemakers in patients with familial dysautonomia–a review of experience with 20 patients. Clin Auton Res 15:15–20PubMedCrossRefGoogle Scholar
  7. 7.
    Goldstein DS, Eisenhofer G, Dunn BB, Armando I, Lenders J, Grossman E, Holmes C, Kirk KL, Bacharach S, Adams R, Herscovitch P, Kopin IJ (1993) Positron emission tomographic imaging of cardiac sympathetic innervation using 6-[18F]fluorodopamine: initial findings in humans. J Am Coll Cardiol 22:1961–1971PubMedCrossRefGoogle Scholar
  8. 8.
    Goldstein DS, Grossman E, Tamrat M, Chang PC, Eisenhofer G, Bacher J, Kirk KL, Bacharach S, Kopin IJ (1991) Positron emission imaging of cardiac sympathetic innervation and function using 18F-6-fluorodopamine: effects of chemical sympathectomy by 6-hydroxydopamine. J Hypertens 9:417–423PubMedCrossRefGoogle Scholar
  9. 9.
    Goldstein DS, Holmes C, Li ST, Bruce S, Metman LV, Cannon RO 3rd (2000) Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med 133:338–347PubMedGoogle Scholar
  10. 10.
    Goldstein DS, Holmes C, Stuhlmuller JE, Lenders JWM, Kopin IJ (1997) 6-[18F]Fluorodopamine positron emission tomographic scanning in the assessment of cardiac sympathoneural function–studies in normal humans. Clin Auton Res 7:17–29PubMedCrossRefGoogle Scholar
  11. 11.
    Goldstein DS, Katzper M, Linares OA, Kopin IJ (2002) Kinetic model for the fate of the sympathoneural imaging agent 6-[18F]fluorodopamine in the human heart: a novel means to assess cardiac sympathetic neuronal function. Naunyn-Schmiedeberg’s Arch Pharmacol 365:38–49CrossRefGoogle Scholar
  12. 12.
    Goodall MC, Gitlow SE, Alton H (1971) Decreased noradrenaline (norepinephrine) synthesis in familial dysautonomia. J Clin Invest 50:2734–2740PubMedCrossRefGoogle Scholar
  13. 13.
    Kashihara K, Ohno M, Kawada S, Okumura Y (2006) Reduced cardiac uptake and enhanced washout of 123I-MIBG in pure autonomic failure occurs conjointly with Parkinson’s disease and dementia with Lewy bodies. J Nucl Med 47:1099–1101PubMedGoogle Scholar
  14. 14.
    Pearson J, Brandeis L, Goldstein M (1979) Tyrosine hydroxylase immunoreactivity in familial dysautonomia. Science 206:71–72PubMedCrossRefGoogle Scholar
  15. 15.
    Pearson J, Dancis J, Axelrod F, Grover N (1975) The sural nerve in familial dysautonomia. J Neuropathol Exp Neurol 34:413–424PubMedCrossRefGoogle Scholar
  16. 16.
    Pearson J, Gallo G, Gluck M, Axelrod F (1980) Renal disease in familial dysautonomia. Kidney Int 17:102–112PubMedCrossRefGoogle Scholar
  17. 17.
    Pearson J, Pytel BA (1978) Quantitative studies of sympathetic ganglia and spinal cord intermedio-lateral gray columns in familial dysautonomia. J Neurol Sci 39:47–59PubMedCrossRefGoogle Scholar
  18. 18.
    Rotstein A, Charrow J, Deal BJ (2007) Documented transient third-degree atrioventricular block and asystole in a child with familial dysautonomia. Pediatr CardiolGoogle Scholar
  19. 19.
    Slaugenhaupt SA, Blumenfeld A, Gill SP, Leyne M, Mull J, Cuajungco MP, Liebert CB, Chadwick B, Idelson M, Reznik L, Robbins C, Makalowska I, Brownstein M, Krappmann D, Scheidereit C, Maayan C, Axelrod FB, Gusella JF (2001) Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 68:598–605PubMedCrossRefGoogle Scholar
  20. 20.
    Slaugenhaupt SA, Mull J, Leyne M, Cuajungco MP, Gill SP, Hims MM, Quintero F, Axelrod FB, Gusella JF (2004) Rescue of a human mRNA splicing defect by the plant cytokinin kinetin. Hum Mol Genet 13:429–436PubMedCrossRefGoogle Scholar
  21. 21.
    Smith AA, Taylor T, Wortis B (1963) Abnormal catechol amine metabolism in familial dysautonomia. N Engl J Med 268:705–707PubMedGoogle Scholar
  22. 22.
    Taki J, Nakajima K, Hwang EH, Matsunari I, Komai K, Yoshita M, Sakajiri K, Tonami N (2000) Peripheral sympathetic dysfunction in patients with Parkinson’s disease without autonomic failure is heart selective and disease specific. Eur J Nucl Med 27:566–573PubMedCrossRefGoogle Scholar
  23. 23.
    Weinshilboum RM, Axelrod J (1971) Reduced plasma dopamine-beta-hydroxylase activity in familial dysautonomia. N Engl J Med 285:938–942PubMedGoogle Scholar
  24. 24.
    Ziegler MG, Lake CR, Kopin IJ (1976) Deficient sympathetic nervous response in familial dysautonomia. N Engl J Med 294:630–633PubMedGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • David S. Goldstein
    • 1
  • Basil Eldadah
    • 1
  • Yehonatan Sharabi
    • 1
  • Felicia B. Axelrod
    • 2
  1. 1.Clinical Neurocardiology SectionNational Institute of Neurological Disorders and Stroke, NIHBethesdaUSA
  2. 2.New York University School of MedicineNew YorkUSA

Personalised recommendations