Journal o f the Autonomic Nervous System. 1 (1979) 119--126
119
© Elsevier/North-Holland Biomedical Press Review Paper l
J
-
,
,
FAMILIAL DYSAUTONOMIA (A BRIEF REVIEW}
JOHN PEARSON
Department of Pathology, New York University Medical Center, 550 First Avenue, New York, N.Y. 10016 (U.S.A.)
(Received July 12th, 1978) (Accepted September 6th, 1979) Key words: familial dysautonomia -- denervation sooersensitivity -- neurons -- ganglia
INTRODUCTION
Familial dysautonomia affects virtually all parts of the nervous system. Inheritance is by autosomal recessive mode and the disease can be diagnosed at birth. There is a tendency for clinical features to worsen with age. Biochemical changes indicate decreased synthesis of noradrenaline. Hyperresponsive:aess to sympathomimetics can be explained by low populations of sympathetic neurons and terminals resulting ".n denervation supersensitivity. Lack of p;urasympathetic neurons is severe in sphenopalatine but minimal in ciiiary ganglia. Sensory ganglia contain few neurons. Bases for central nervous system dysfunction and the pathophysiology of the disease remain to be discovered. Familia! dysautonomia, which is also known as the Riley--Day s y n d r o m e was first described in 1949 [31] and has since been found to have autosomat recessive inheritance [5]. While autonomic symptoms, sigl,s and biochemical manifestations are prominent this is a disease which affects many other nervous and general somatic systems. The following review relies heavily on experience gained at the Familial Dysautonomia Treatment and Evaluatio3~ Center at New York University Medical Center where over 190 patien~ are re~stered. CLINICAL DA.TA
Inability to suck is usually the first 'autonomic' symptom to be recognized; often infants must be tube fed. Poor co.oldination of swallowing persists throughout life and resultant regurgitation, aspiration and pn,~t,monia may be life-threatening [ 15,19]. Episodic vomiting, which is often severe enough to cause dehydratic,n, occurs in approximately 40% of patients [3]. Motility of the gut, particu-
120
larly its upper portion, is severely diminished and bowel and bladder distent:Dns are common during vomiting crises. These crises, associated with negativistic behavior, hypertension, tachycardia and diaphoresis, occur after 3 years of age. On the basis of these signs familial dysautonomia (FD) p~tients have been mistakenly diagnosed as having pheochromocytom~s [18]. Emotional outbursts may also occur during crises. Agitation, hsomnia, depression, facial grimacing, tongue thrusting and rhythmic body movements are features of the disease. Poor control of body temperature is frequent; hypothermia and hyperthermia occur. As a group, patients tend to have average scores on intelligence tests [38] but low scores are obtained by those who continue beyond 4 years of age to have repeated breath-holding spells severe enough to cause cyanosis [2]. Epile',~tiform electroencephalograms have been reported [3]. Sei:~ures with decerebrate posturing sometimes occur during breath-holding when the electroencephalogram is normal. During periods of quiesence postural hypotension occurs and may be severe enough to cause syncope [3]. Profound cardiac slowing ("vago-vagal reflex") has been seen post-micturition and with laryngeal intubation. Occasionally it has been severe enough to result in respiratory and cardiac arrest. Low doses of cholinomimetics such as methacholine produce marked falls in blood pressure without compensatory tachycardia [37]. Doses of infused norepinephrine which would normally be sub-threshold lead to marked elevation of blood l:,ressure without bradycardia [33]. The pupil is supersensitive to constriction by methacholine but not to dilation by epinephrine [34]. Patients with FD can have moist lacrimal beds but do not usually form overflow tears. Low doses of methacholine have been reported to cause transient tearing, to temporarily restore the flare response to intradermal histamine and to cause the appearance of cleep tendon reflexes [37 ]. There are abnormal responses to altered a~mospheric gas content [9,10]. Hypercapnea and hypoxia do not cause ap pl ~priate increases in respiratory efforts. Comas or rapid deaths of FD patie nt~; have occurred in tunnels and at high altitudes [3]. Drowning may occur wi~en air hunger is not perceived under water. Apnea has been observed at ncrmal atmospheres and is associated with fluctuating respiratory patterns during sleep [3]. Sensory abnormalities in FD include con,eal hypesthesia, poor perception of pain and marked bhmting of ~empera;ure detection. Traditionally included with sensory abnormalities is ~,heabsr. n~e of a flare response to intradermal histamine, a cardinal sign of FD (see ref. 35). In older patients poor proprioception sometimes leads to a positive Romberg sign. Decreased vestibular responses may be detected by a spinning test. Tendon reflexes are diminished or absent. Poor co-ordination of postural muscles usually leads to marked scoliosis at an early age. Abnormal conduc-
121 tion velocity, biphasic recorded signals and decreased evoked potentials are observed in sensory nerves [ 1 G], The tongue is smooth and lacks fungiform papillae [36]. Circumvallate papillae are hypoplastic [24]. General somatic growth is poor [3] but growth hormone levels are found to be normal [7]. Decreased "insulin" levels have been detected by radioimmunoassay but glucose tf,l~rance curves are normal [7]. Female patients with FD have an average delay of about two years in the onset of puberty. Nevertheless, they have been shown to ~vulate normally and are capable of conceiving and carrying pregnancies to term
[29]. Progressive diminution of renal function is a frequent observation [25]. Many patients have subnormal renin secretion [30]. Nocturnal enoresis is commonly seen into the teens and nocturia usually occurs thereafter [3]. Urine volume increases at night. BIOCHEMICAL DATA Norepinephrine and epinephrine catabolite excretion is diminished but dopamine products continue to be excreted in normal amounts [12l. There is a 60% diminution in norepinephrine synthesis [1.2] and the total body pool of norepinephrine is small [8]. Such observations might have suggestecl that a block occurs in the synthesis of epinephrine and norepinephrine from dopamine, but radioisotope studies failed to demonstrate such a block [8]. A report of diminished dopamine-~-hydroxylase (DBH) levels in FD [39] was not strongly supported when vn independent set of observations was matched with appropriate controls [11]. Normally norepinephrine and DBH increase on standing but this does not happen in FD [40]. During emotional crises plasma norepinephrine and dopamine are markedly elevated and there are lesser rises in epinephrine [2]. During such crises vomiting usually coincides with high dopamine levels. Hypertension correlates best with norepinephrine levels. Valium sedates patients in crises and relieves vomiting, possibly by blocking the actiohs of dopamine and norepinephrine. Its use is followed by lowering of plasma dopamine. PATHOLOGIC DATA Superior cervical sympathetic ganglia are hypoplastic with mean volumes 34% of normal and mean neuronal counts 12% of nolmal [26]. Other sympathetic ganglia show similar changes. Surviving neurons tend to be slightly increased in size. Degenerative changes are not promirtent but there tend to be fewer neurons in older patients. Neuroblast-like ceils seen in a 1 year old patient [22] were not found in 10 others with ages ranging from 3 to 33 years. ST~riving sympathetic neurons have a higher c(~ntent than normal of immunoreactive tyrosine hydroxylase (TH) (see ref. 20 }. It has not been possible to demonstrate sympathetic terminals by
122
aldehyde-induced catecholamine fluorescence in FD (see ref. 13). Nor has it been possible to show dense core containing terminal varicosities in relationship to blood vessels [13, 25]. Patients have about half the normal population of sympathetic preganglionic neurons in the intermedio-lateral columns of the spinal cord [26]. The most severely depleted neuronal populations yet found in FD have been in the parasympathetic sphenopalatine ganglia [27]. Ciliary ganglia are normal or show minor depletions of neurons [27]. Lingual subn/ucosal neurons and sensory axons are depleted [ 14]. Circumvallate papillae are hypoplastic and the population of taste buds is small. Sensory neurons in spinal ganglia are few in number in young patients with FD and there is evidence for continuing degeneration with increasing age [28]. Spinal cord dorsal column tissues progressively diminish in crosssection in older patients [28]. The dorsal root entry zones and Lissauer's tracts are hypop.iastic. Within the sensory sural nerve there are severe diminutions in populations of small myelinated and unmyelinated axens and lesser reductions of large myelinated axons [1,23]. The overall a x o n c o n t e n t is diminished and the nerve fails to increase in size with age [23]. There has been a single observation of selective diminution of gamma motoneurons in FD (see ref. 17). We have found histochemical type grouping, a characteristic of chronic m o t o r neuron disorders, in a small number of samples c f paraspinal muscles in FD. No consistent central nervous system changes have been found by qualitative methods. Within the kidney there is worsening glomerulosclerosis with age and vascular autonomic terminals cannot be demonstrated [ 25 ]. DISCUSSION
Abnormalities of emotion and intellectual development suggest involvement of the central nervous system in FD. So also does the observed beneficial effect of neuroleptic drugs. The CNS is the most likely source for the increase of circulating dopamine observed during vomiting crises. Abnormalities in CNS processing may be involved in poor temperature control, poor suck, vomiting crises, apnea and abnormal responses to altered blood acidity or oxygen tension, although it should be remembered that peripheral sensory or motor components of reflexes may also malfunction. Peripheral sympathetic denervation provides a good explanation for postural hypotension. Lack of sympathetic balance to vagal reflexes might account for cardiac arrest on tracheal intubation by a mechanism analagous to that suggested for tetraplegic patients [6]. A similar process may underlie the marked bradycardia which sometimes follows micturition. Sympathetic terminals are the main site of norepinephrine metabolism. Their anatomic depletion accounts for diminished catecholamine synthesis in the absence of demonstrable abnormalities in synthetic enzyme functions. Such terminals are normally the source of increments of N~ and DBH on
123
standing. Thus absence of this response in F D is also explained. Skin blotching and hypertension during excitement m a y be an exaggerated response to catecholamines released from the adrenal medulla which appears to be functionally normal in FD. This and the marked effect of very low doses of norepinephrine [33] are accounted for by denervaticn supersensitivity at sympathetic effector sites. Curiously, however, the pupil is not sensitive to epinephrine despite the fact that superior cervical sympathetic ganglia have very low neuronal populations. The pupil is supersensitive to methacholine. Since the ciliary ganglia are normal or only minimally depleted of neurons, denervation hypersensitivity is unlikely to be involved. Another parasympathetic anomally, the lack of overflow tears is accounted for by diminution of neurons in sphenopalatine ganglia. Lack of renal sympathetic nerves must diminish the ability of the kidney to adjust hemodynamicaily for the alterations in blood pressure and volume which are c o m m o n in FD. Resultant glomerular ischemia m a y be the cause of progressive glomerulosclerosis in FD. Renal autonomic denervation accounts for diminished renin secretion. Increased tyrosine hydroxylase is demonstrated in the few remaining sympathetic netu'ons by biochemical and immunohistochemical techniques. This increase might represent either a functional compensation for decreased neuron number or a damming back of enzyme in cells bereft of peripheral axons. Sensory neuron deficits account for blunting of pain and temperature sensitivity. Progressive degeneration of larger neurons, which are initially spared, is reflected in con~nuing posterior column degeneration and correlates with the late clinical appearance of proprioceptive anomalies. Attenuation of tendon reflexes may also have a sensory component in addition to the gamma motor neuron deficit which has been reported. Absence of sensory axons removes an important component of the axon reflexive flare response to intradermal histamine. F U T U R E STUDIES Search for central nervous system abnormalities should continue. The recent application of immunohistochemistry for demonstration of central catecholaminergic neurons [21] makes it possible to plan selective quantitative studies. In view of anomalous respiratory responses to altered blood chemistry peripheral chemoreceptors should be examined. The clinical and pathologic features of F D indicate that neuronal deficits are present at birth and that slow degenerative changes occur thereafter. Thus it is postulated that there is a deficit in atrophic mechanism essential in antenatal development which continues to have a relatively minor sustaining function postnataUy. Abnormal nerve growth factor (NGF) function might account for changes in sensory and sympathetic neurons. A report of
124
increased circulating/~-NGF levels in FD (see ref. 32), has led us to begin a search for abnormalities in NGF receptors. Cultured fibroblasts from FD patients produce slightly less radioimmunoassayable NGF than those of healthy controls or patients with dystonia [4]. The biological activity of this NGF is about 12% of normal [4]. The possibility that an abnormality in NGF protein structure occurs in FD should be studi~d. Since NGF is not now known to effect all systems which are abnormal in FD the functional and trophic interrelationships of those systems and their susceptibility to NGF and other growth factors should be examined. More information is needed regarding development of parasympathetic ganglia. A possible relationship between the observed nervous system deficits and poor general somatic growth should be examined. Objective mea~urement of clinical abnormalities would permit the natural course of the disease and its modification by supportive therapy to be evaluated. More pharmacologic data are needed concerning the nature and extent of supersensitivity to sympathomimetic and parasympathomimetic drugs. In view of the normal (or minimally abnormal) morphology of ciliary ganglia repeated study of pupillary responses would be particularly valuable. More data are required concerning alterations in circulating catecholamines. Improved therapeutic techniques are needed for the attenuation of crises and to slow the long-term degenerative changes which occur. Development of an animal model would aid in the study of pathophysiology and the development of therapeutic measures. SUMMARY
Familial dysautonomia presents fascinating challenges to neuroscientists. Many of the clinical and biochemical features are now explicable in terms of pathologic aeficits in peripheral autonomic and sensory neurons but much remains to be learned regarding central nervous system function in this disease. No firmly established data are available regarding the etiology of the developmental and degenerative changes in neurons in FD. Modem medical care permits survival of increasing numbers of patients into adulthood. Greater knowledge of the biochemistry and pharmacology of FD is required so that supportive therapy can be designed to increase the quality of life for patients and diminish the degenerative changes which inexorably lead to their deaths. ACKNOWLEDGEMENTS
Many of the studies on which this review is based were generously supported by the Dysautonomia Foundation and by NIH Grant RO1 HO 12260. REFERENCES
1 Aguayo, A., Nail C.P.V. and Bray, G.M., Peripheral nelwe abnormalities in the Riley-Day syndrome, Arch. Neurol., (Chic.), 24 ( 1971 ) 106--116.
125 2 Axelrod, F.B. personal communication. 3 Axelrod, F.B., Nachtigal, R. and Dancis, J., Familial dysautonomia: diagnosis, pathogenesis and management, Advanc. Pediat., 21 (1974). 4 Breakfield, X. and Schwartz J., Data p:esented at the Winter Brain Conference and the Dysautonomia Foundation Research Reporting Session, 1979. 5 Brunt, P.W. and McKusick, V.A., Familial dysautonomia, A report of genetic and clinical studies, with a review of the literature, Medicine (Baltimore), 49 (1970) 343. 6 Christensen, N.J., Frankel, H.L., Mathias, C.J. and Spalding, J.M.K., Enhanced pressure response to noradrenaline in human subjects with chronic sympathetic decentralization, J. Physiol, (Lond.) 252 ( 1975) 39--40. 7 Cole, H.S., Demonstration of insulopenia in familial dysautonomia, Pediatrics, 52 137. 8 DeQuattro, V. and Linde, L., Intact synthesis and increased turnover of norepinephrine-3H after L-DOPA 3H in dysautonomia, Clin. Res., 17 (1969) 237. 9 Edelman, N.H., Cherniack, N.S., Lahiri, S., Riehards, E. and Fishman, A.P., The effects of abnormal sympathetic nervous function upon the ventilatory response to hypoxia, J. clin. Invest., 41 (1970) 1155. 10 Filler, J., Smith, A.A., Stone, S. and Dancis, J., Respiratory control in familial dysautonomia, J. Pediat., 66 (1965) 509. 11 Freedman, L., Ruffman, M., Goldstein, M., Axelrod, F.B. and Dancis, J., unpl~blished data. 12 Goodall, G., Gitlow, S.E. and Alton, H., Decreased noradrenaline synthesis in F.D., J. clin. Invest., 50 (1971) 2734--2740. 13 Grover-Johnson, N. and Pearson, J., Deficient vascular innervation in familial dysautonomia, an explanation for vasomotor instability, Neurop~th. appl. Neurobiol., 2 (1976) 217--224. 14 Grover-Johnson, N. and Pearson, J., Submucosal neurons associated with taste buds in circumvallate papillae of the huma:~ t,~ngue, J. Cell Biol., 70 (1976) 160. 15 Gyepes, M. and Linde, L., Familial dysautonomia: the mechanism of aspiration, Radiology 91 (1968) 471. 16 Iyer, K., Axelrod, F.B., Ma, D., Merkin, H., Spielholtz, N. and Goodgold, J., Nerve conduction and somatosensory evoked potentials in familial dysautonomia, 6th International Congres.~ Electromyography, Stockholm, 1979. 17 Kawamura, Y., Dyck, P.J., Low, P.A. and Shimono, M., The number and sizes of' reconstructed peripheral autonomic sensory and motor neurons in a case of dysautonomia, J. Neuropath, exp. Neurol., 37 (1978) 741--755. 18 Manger, W.M. and Gifford, R.W., Pheochromocytoma, Springer Verlag, New York, 1977. 19 Margulies, S.I., Brunt, P., Donner, M. and Silbinger, M., Familial dysautonomia: a cineradiographic study of the swallowing mechanism, Radiolo~,, 90 (1968) 107 20 Pearson, J., Brandeis, L. and Goldstein, M, Tyro~me hydroxylase immunoreac~ivity, Science, 206 (1979) 71--72. 21 Pearson, J., Goldstein, M. and Brandeis, L., Tyrosine hydroxylase immunohistochemistry in h t m a n brain, Brain Res., 165 (1979) 333--337. 22 Pearson, J., A::elrod, F. and Dancis, J., Current concepts of dysautonomia: nemo. pathological defects, Ann. N.Y. Acad. qci., 228 (1974) 288--300. 23 Pearson, J., Dancis, J., Axelrod, F. and Grover, N., The sural nerve in famihai dysautonomia, J. Neuropath. exp. Nemol., 34 (1975) 413--424. 24 Pearson, J., Finegold, M. and Budzilovich, G., The tongue and taste in familial dysautonomia, Pediatrics, 45 (1970) 739. 25 Pearson, J., GaUo, G., Gluck, M. and Axelrod, F., Renal di:;ease in familial d:,sautonomia, Kidney Int., in press. 26 Pearson, J. and Pytel, B., Quantitative studies of sympathetic ganglia and spinal cord
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27 28 29 30 31 32 33 34 35 36 37 38 39 40
itttermedio-lateral gray columns in familial dysautonomia, J. Neurol. Sci., 39 (1978) 47--59. Pearson, J. and Pytel, B., Quantitative studies of ciliary and sphenopalatine ganglia in fnmilial dysautonomia, J. Neurol. Sci., 39 (1978) 123--130. P~arson, J., Pytel, B., Grover-Johnson, N., Axeirod, F. and Dancis, J., Quantitative studies of dorsal root ganglia and neuropathologic observations on spinal cords in f~milial dysautonomia, J. Neurol. Sci., 35 (1978) 77--92. Porges, R.F., Axeirod, F B. and Richards, M., Pregnancy in familial dysautonomia, Amer. J. Obstet. Gynec., 132 (1978) 485--488. R:lbinowitz, D., Landau, H., Rosier, A., Moses, S.W., Rotem, Y. and Freier, S., Plasma renin activity and aldosterone in familial dysautonomia, Metaboli.~;m, 23 (1974) 1--5. Riley, C.M., Day, R.L., Greely, D. MeL. and Langford, W.S. Central autonomic dysfunction with defective lacrimation, Pediatrics 3 (1949) 468. Siggers, S.C., Rogers, J.G., Boyer, S.H., Margolet, L, Dorkin. H., Banarjee, S.P and Shooter, E.M., Increased nerve growth factor ~-chain cross reacting material in familial d~:sautonomia, New Engl. J. Med., 295 (1976) 629--634. Smith, A.A. and Dancis, J., Exaggerated response to infused norepinephrine in familial dysautonomia, New Engl. J. Med., 270 (1964) 704--707. Smith, A.A., Daacis, J. and Breinin, C,., Ocular responses to autonomic drugs in familial dysautonomia, Invest. Ophthal., 4 (1965) 358. Smith, A.A. and Daneis, J., Response to intradermal histamine in familial dysautonomia--a diagnostic test, J. Pediat., 63 (1963) 889. Smith, A.A., Farbman, A. and Dancis, J., Tongue it. familial dysautonomia. A diagnostic sign, Amer. J. Dis. Child., 110 (1965) 152. Smith, A..4., Hirsch, J.I. and Daneis, J., Responses to infused methacholine in familial dysautonomia, Pediatrics 36 (1965) 225. Welton, W., Clayson, D., Axelrod, F. and Levine, D.B., Intellectual development in familial dysautonomia, Pediatrics, 63 (1979) 708--712. Weinshilbaum, R.M. and Axelrod, F., Reduced plasma dopamine ~-hydroxylase activity in familial dysautonomia, New Engl. J. Med., 285 (1971) 938. Zieglel', M.G., Lake, R.C. and Kopin, I.J., Deficient sympathetic nervous response in familial dysautonomia, New Engl. J. Med.~ 294 (1976) 630--633.
119
© Elsevier/North-Holland Biomedical Press Review Paper l
J
-
,
,
FAMILIAL DYSAUTONOMIA (A BRIEF REVIEW}
JOHN PEARSON
Department of Pathology, New York University Medical Center, 550 First Avenue, New York, N.Y. 10016 (U.S.A.)
(Received July 12th, 1978) (Accepted September 6th, 1979) Key words: familial dysautonomia -- denervation sooersensitivity -- neurons -- ganglia
INTRODUCTION
Familial dysautonomia affects virtually all parts of the nervous system. Inheritance is by autosomal recessive mode and the disease can be diagnosed at birth. There is a tendency for clinical features to worsen with age. Biochemical changes indicate decreased synthesis of noradrenaline. Hyperresponsive:aess to sympathomimetics can be explained by low populations of sympathetic neurons and terminals resulting ".n denervation supersensitivity. Lack of p;urasympathetic neurons is severe in sphenopalatine but minimal in ciiiary ganglia. Sensory ganglia contain few neurons. Bases for central nervous system dysfunction and the pathophysiology of the disease remain to be discovered. Familia! dysautonomia, which is also known as the Riley--Day s y n d r o m e was first described in 1949 [31] and has since been found to have autosomat recessive inheritance [5]. While autonomic symptoms, sigl,s and biochemical manifestations are prominent this is a disease which affects many other nervous and general somatic systems. The following review relies heavily on experience gained at the Familial Dysautonomia Treatment and Evaluatio3~ Center at New York University Medical Center where over 190 patien~ are re~stered. CLINICAL DA.TA
Inability to suck is usually the first 'autonomic' symptom to be recognized; often infants must be tube fed. Poor co.oldination of swallowing persists throughout life and resultant regurgitation, aspiration and pn,~t,monia may be life-threatening [ 15,19]. Episodic vomiting, which is often severe enough to cause dehydratic,n, occurs in approximately 40% of patients [3]. Motility of the gut, particu-
120
larly its upper portion, is severely diminished and bowel and bladder distent:Dns are common during vomiting crises. These crises, associated with negativistic behavior, hypertension, tachycardia and diaphoresis, occur after 3 years of age. On the basis of these signs familial dysautonomia (FD) p~tients have been mistakenly diagnosed as having pheochromocytom~s [18]. Emotional outbursts may also occur during crises. Agitation, hsomnia, depression, facial grimacing, tongue thrusting and rhythmic body movements are features of the disease. Poor control of body temperature is frequent; hypothermia and hyperthermia occur. As a group, patients tend to have average scores on intelligence tests [38] but low scores are obtained by those who continue beyond 4 years of age to have repeated breath-holding spells severe enough to cause cyanosis [2]. Epile',~tiform electroencephalograms have been reported [3]. Sei:~ures with decerebrate posturing sometimes occur during breath-holding when the electroencephalogram is normal. During periods of quiesence postural hypotension occurs and may be severe enough to cause syncope [3]. Profound cardiac slowing ("vago-vagal reflex") has been seen post-micturition and with laryngeal intubation. Occasionally it has been severe enough to result in respiratory and cardiac arrest. Low doses of cholinomimetics such as methacholine produce marked falls in blood pressure without compensatory tachycardia [37]. Doses of infused norepinephrine which would normally be sub-threshold lead to marked elevation of blood l:,ressure without bradycardia [33]. The pupil is supersensitive to constriction by methacholine but not to dilation by epinephrine [34]. Patients with FD can have moist lacrimal beds but do not usually form overflow tears. Low doses of methacholine have been reported to cause transient tearing, to temporarily restore the flare response to intradermal histamine and to cause the appearance of cleep tendon reflexes [37 ]. There are abnormal responses to altered a~mospheric gas content [9,10]. Hypercapnea and hypoxia do not cause ap pl ~priate increases in respiratory efforts. Comas or rapid deaths of FD patie nt~; have occurred in tunnels and at high altitudes [3]. Drowning may occur wi~en air hunger is not perceived under water. Apnea has been observed at ncrmal atmospheres and is associated with fluctuating respiratory patterns during sleep [3]. Sensory abnormalities in FD include con,eal hypesthesia, poor perception of pain and marked bhmting of ~empera;ure detection. Traditionally included with sensory abnormalities is ~,heabsr. n~e of a flare response to intradermal histamine, a cardinal sign of FD (see ref. 35). In older patients poor proprioception sometimes leads to a positive Romberg sign. Decreased vestibular responses may be detected by a spinning test. Tendon reflexes are diminished or absent. Poor co-ordination of postural muscles usually leads to marked scoliosis at an early age. Abnormal conduc-
121 tion velocity, biphasic recorded signals and decreased evoked potentials are observed in sensory nerves [ 1 G], The tongue is smooth and lacks fungiform papillae [36]. Circumvallate papillae are hypoplastic [24]. General somatic growth is poor [3] but growth hormone levels are found to be normal [7]. Decreased "insulin" levels have been detected by radioimmunoassay but glucose tf,l~rance curves are normal [7]. Female patients with FD have an average delay of about two years in the onset of puberty. Nevertheless, they have been shown to ~vulate normally and are capable of conceiving and carrying pregnancies to term
[29]. Progressive diminution of renal function is a frequent observation [25]. Many patients have subnormal renin secretion [30]. Nocturnal enoresis is commonly seen into the teens and nocturia usually occurs thereafter [3]. Urine volume increases at night. BIOCHEMICAL DATA Norepinephrine and epinephrine catabolite excretion is diminished but dopamine products continue to be excreted in normal amounts [12l. There is a 60% diminution in norepinephrine synthesis [1.2] and the total body pool of norepinephrine is small [8]. Such observations might have suggestecl that a block occurs in the synthesis of epinephrine and norepinephrine from dopamine, but radioisotope studies failed to demonstrate such a block [8]. A report of diminished dopamine-~-hydroxylase (DBH) levels in FD [39] was not strongly supported when vn independent set of observations was matched with appropriate controls [11]. Normally norepinephrine and DBH increase on standing but this does not happen in FD [40]. During emotional crises plasma norepinephrine and dopamine are markedly elevated and there are lesser rises in epinephrine [2]. During such crises vomiting usually coincides with high dopamine levels. Hypertension correlates best with norepinephrine levels. Valium sedates patients in crises and relieves vomiting, possibly by blocking the actiohs of dopamine and norepinephrine. Its use is followed by lowering of plasma dopamine. PATHOLOGIC DATA Superior cervical sympathetic ganglia are hypoplastic with mean volumes 34% of normal and mean neuronal counts 12% of nolmal [26]. Other sympathetic ganglia show similar changes. Surviving neurons tend to be slightly increased in size. Degenerative changes are not promirtent but there tend to be fewer neurons in older patients. Neuroblast-like ceils seen in a 1 year old patient [22] were not found in 10 others with ages ranging from 3 to 33 years. ST~riving sympathetic neurons have a higher c(~ntent than normal of immunoreactive tyrosine hydroxylase (TH) (see ref. 20 }. It has not been possible to demonstrate sympathetic terminals by
122
aldehyde-induced catecholamine fluorescence in FD (see ref. 13). Nor has it been possible to show dense core containing terminal varicosities in relationship to blood vessels [13, 25]. Patients have about half the normal population of sympathetic preganglionic neurons in the intermedio-lateral columns of the spinal cord [26]. The most severely depleted neuronal populations yet found in FD have been in the parasympathetic sphenopalatine ganglia [27]. Ciliary ganglia are normal or show minor depletions of neurons [27]. Lingual subn/ucosal neurons and sensory axons are depleted [ 14]. Circumvallate papillae are hypoplastic and the population of taste buds is small. Sensory neurons in spinal ganglia are few in number in young patients with FD and there is evidence for continuing degeneration with increasing age [28]. Spinal cord dorsal column tissues progressively diminish in crosssection in older patients [28]. The dorsal root entry zones and Lissauer's tracts are hypop.iastic. Within the sensory sural nerve there are severe diminutions in populations of small myelinated and unmyelinated axens and lesser reductions of large myelinated axons [1,23]. The overall a x o n c o n t e n t is diminished and the nerve fails to increase in size with age [23]. There has been a single observation of selective diminution of gamma motoneurons in FD (see ref. 17). We have found histochemical type grouping, a characteristic of chronic m o t o r neuron disorders, in a small number of samples c f paraspinal muscles in FD. No consistent central nervous system changes have been found by qualitative methods. Within the kidney there is worsening glomerulosclerosis with age and vascular autonomic terminals cannot be demonstrated [ 25 ]. DISCUSSION
Abnormalities of emotion and intellectual development suggest involvement of the central nervous system in FD. So also does the observed beneficial effect of neuroleptic drugs. The CNS is the most likely source for the increase of circulating dopamine observed during vomiting crises. Abnormalities in CNS processing may be involved in poor temperature control, poor suck, vomiting crises, apnea and abnormal responses to altered blood acidity or oxygen tension, although it should be remembered that peripheral sensory or motor components of reflexes may also malfunction. Peripheral sympathetic denervation provides a good explanation for postural hypotension. Lack of sympathetic balance to vagal reflexes might account for cardiac arrest on tracheal intubation by a mechanism analagous to that suggested for tetraplegic patients [6]. A similar process may underlie the marked bradycardia which sometimes follows micturition. Sympathetic terminals are the main site of norepinephrine metabolism. Their anatomic depletion accounts for diminished catecholamine synthesis in the absence of demonstrable abnormalities in synthetic enzyme functions. Such terminals are normally the source of increments of N~ and DBH on
123
standing. Thus absence of this response in F D is also explained. Skin blotching and hypertension during excitement m a y be an exaggerated response to catecholamines released from the adrenal medulla which appears to be functionally normal in FD. This and the marked effect of very low doses of norepinephrine [33] are accounted for by denervaticn supersensitivity at sympathetic effector sites. Curiously, however, the pupil is not sensitive to epinephrine despite the fact that superior cervical sympathetic ganglia have very low neuronal populations. The pupil is supersensitive to methacholine. Since the ciliary ganglia are normal or only minimally depleted of neurons, denervation hypersensitivity is unlikely to be involved. Another parasympathetic anomally, the lack of overflow tears is accounted for by diminution of neurons in sphenopalatine ganglia. Lack of renal sympathetic nerves must diminish the ability of the kidney to adjust hemodynamicaily for the alterations in blood pressure and volume which are c o m m o n in FD. Resultant glomerular ischemia m a y be the cause of progressive glomerulosclerosis in FD. Renal autonomic denervation accounts for diminished renin secretion. Increased tyrosine hydroxylase is demonstrated in the few remaining sympathetic netu'ons by biochemical and immunohistochemical techniques. This increase might represent either a functional compensation for decreased neuron number or a damming back of enzyme in cells bereft of peripheral axons. Sensory neuron deficits account for blunting of pain and temperature sensitivity. Progressive degeneration of larger neurons, which are initially spared, is reflected in con~nuing posterior column degeneration and correlates with the late clinical appearance of proprioceptive anomalies. Attenuation of tendon reflexes may also have a sensory component in addition to the gamma motor neuron deficit which has been reported. Absence of sensory axons removes an important component of the axon reflexive flare response to intradermal histamine. F U T U R E STUDIES Search for central nervous system abnormalities should continue. The recent application of immunohistochemistry for demonstration of central catecholaminergic neurons [21] makes it possible to plan selective quantitative studies. In view of anomalous respiratory responses to altered blood chemistry peripheral chemoreceptors should be examined. The clinical and pathologic features of F D indicate that neuronal deficits are present at birth and that slow degenerative changes occur thereafter. Thus it is postulated that there is a deficit in atrophic mechanism essential in antenatal development which continues to have a relatively minor sustaining function postnataUy. Abnormal nerve growth factor (NGF) function might account for changes in sensory and sympathetic neurons. A report of
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increased circulating/~-NGF levels in FD (see ref. 32), has led us to begin a search for abnormalities in NGF receptors. Cultured fibroblasts from FD patients produce slightly less radioimmunoassayable NGF than those of healthy controls or patients with dystonia [4]. The biological activity of this NGF is about 12% of normal [4]. The possibility that an abnormality in NGF protein structure occurs in FD should be studi~d. Since NGF is not now known to effect all systems which are abnormal in FD the functional and trophic interrelationships of those systems and their susceptibility to NGF and other growth factors should be examined. More information is needed regarding development of parasympathetic ganglia. A possible relationship between the observed nervous system deficits and poor general somatic growth should be examined. Objective mea~urement of clinical abnormalities would permit the natural course of the disease and its modification by supportive therapy to be evaluated. More pharmacologic data are needed concerning the nature and extent of supersensitivity to sympathomimetic and parasympathomimetic drugs. In view of the normal (or minimally abnormal) morphology of ciliary ganglia repeated study of pupillary responses would be particularly valuable. More data are required concerning alterations in circulating catecholamines. Improved therapeutic techniques are needed for the attenuation of crises and to slow the long-term degenerative changes which occur. Development of an animal model would aid in the study of pathophysiology and the development of therapeutic measures. SUMMARY
Familial dysautonomia presents fascinating challenges to neuroscientists. Many of the clinical and biochemical features are now explicable in terms of pathologic aeficits in peripheral autonomic and sensory neurons but much remains to be learned regarding central nervous system function in this disease. No firmly established data are available regarding the etiology of the developmental and degenerative changes in neurons in FD. Modem medical care permits survival of increasing numbers of patients into adulthood. Greater knowledge of the biochemistry and pharmacology of FD is required so that supportive therapy can be designed to increase the quality of life for patients and diminish the degenerative changes which inexorably lead to their deaths. ACKNOWLEDGEMENTS
Many of the studies on which this review is based were generously supported by the Dysautonomia Foundation and by NIH Grant RO1 HO 12260. REFERENCES
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