131

Rett Syndrome: Stimulation of Endogenous Biogenie Amines * By R. Pelligra 1, R. D. Norton2, Roselise Wilkinson2, H. A. Leon1 and W. R. Matson 3

Abstract Transient hypercapnic hyperoxemia was induced in two Rett syndrome children by the administration of a gaseous mixture of 80 % 02 and ~o % CO 2. Time course studies of neurotransmitters and their metabolites showed an immediate and marked increase in central biogenic amine turnover following inhalation of the gas mixture. The increased turnover of biogenic amines was associated with improved clinical changes. This suggests a coupled relationship and provides further support for an etiological role of neurotransmitter dysfunction in Rett syndrome. In a complementary study, elevation of pulmonary CO 2 by application of a simple rebreathing device resulted in improvement of abnormal blood gases and elimination of the Cheyne-Stokes-like respiratory pattern of the Rett syndrome. Near normalization of the EEG occurred when a normal respiratory pattern was imposed by means of a respirator. Taken together, these results lead to the preliminary conclusion that cerebral hypoxemia secondary to abnormal respiratory function may contribute to diminished production of biogenic amines in Rett syndrome.

Keywords

Rett syndrome - Neurotransmitters - Biogenic amines - Hypoxia - Hypocapnia - Cheyne-Stokes respiration Zusammenfassung Bei zwei an Rett-Syndrom leidenden Kindern wurde durch Einatmung eines Gasgemisches von 80 % Sauerstoff und 20 0A> Kohlendioxid eine vorübergehende hyperkapnische Hyperoxämie erzeugt. Dabei wurde der Zeitverlauf der Aktivität von Neurotransmittern und ihrer Meta-

boliten untersucht und eine sofortige, deutliche Erhöhung des Umsatzes zentraler biogener Amine nach Beginn der Einatmung des Gasgemisches festgestellt. Dieser erhöhte Umsatz war mit einer Verbesserung der klinischen Symptomatik verbunden, was einen Kausalzusammenhang nahelegt und Befunde über die ätiologische Rolle eines gestörten Transmitterhaushaltes bei Patienten mit Rett-Syndrom unterstützt. In einer ergänzenden Studie wurde der pulmonale CO2-Partialdruck durch eine einfache Rückatmungsvorrichtung gesteigert und eine Verbesserung der abnormen Blutgaswerte sowie Aufhebung des Cheyne-Stokes-artigen Atmungsmusters erzielt. Weiters resultierte aus der Herstellung eines physiologischen Atemmusters mittels Respirator und führte zu einer weitgehenden Normalisierung des elektroenzephalographischen Befundes. Zusammenfassend sprechen diese vorläufigen Befunde an zwei Patienten mit Rett-Syndrom für eine Beteiligung atmungsbedingter zerebraler Hypoxämie an der abnorm geringen zentralen Bildung biogener Amine. Resume Une hyperoxie hypercapnique transitoire a ete indute chez deux enfants atteints d'un syndrome de Rett par l'administration d'un melange gazeux contenant 80 % d'02 et 20 % de CO 2 . L'etude de la cinetique de liberation des neurotransmetteurs et de leurs metabolites a montre une augmentation immediate et marquee du turn-over des amines biogenes centrales a la suite de l'inhalation du melange gazeux. Cet accroissement du turn-over des amines biogenes s'est double d'une amelioration clinique, suggerant une interrelation entre les deux phenomenes, et apportant un argument supplementaire en faveur d'un röle etiologique du dysfonctionnement du turn-over des neurotransmetteurs dans le syndrome de Rett. Lors d'une etude complementaire, l'elevation du CO2 pulmonaire par application d'un systeme de res-

Received April 11, 1991; accepted May 30,1991 Neuropediatrics 23 (1992) 131-137 © Hippokrates Verlag Stuttgart

* Supported in part by NASA JO-G1145 and the Edward B. LeWinn Children's Award.

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1Ames Research Center, The National Aeronautics and Space Administration (NASA), Moffett Field, CA 94035, USA, 2Respiratory Physiology Laboratory, The Institutes for the Achievement of Human Potential, 8801 Stenton Avenue, Philadelphia, PA 19118, USA, and 3ESA Laboratories, 45 Wiggins Ave., Bedford, MA 01173, USA

Neuropediatrics 23 (1992)

piration en circuit ferme a entraine und amelioration de la gazometrie anormale chez ces enfants et I'elimination du tableau respiratoire de type Cheyne-Stokes observe dans le syndrome de Rett. On a aussi note une quasi-normalisation de I'EEG lorsqu'une respiration normale etait imposee par I'intermediaire d'un respirateur. L'ensemble de ces resultats nous conduit a profuser la conclusion preliminaire suivante: I'hypoxie cerebrale secondaire a une fonction respiratoire anormale pourrait contribuer a une diminution de la production d'amines biogenes dans le syndrome de Rett.

Resumen

A dos nifias con sindrome de Rett se les administr6 una mezcla gaseosa de 80 % de O2 y 20 % CO 2 con el prop6sito de inducir una hiperoxemia hipercapnica transitoria. Luego de la inhalaci6n de la mezcla gaseosa, los estudios de neurotransmisores y sus metabolitos realiza-

Introduction

Andreas Rett, in 1966 (23), first described the symptom complex that now bears his name. Children afflicted with this slowly progressive, degenerative disorder are exclusively female and characteristically exhibit autism, mental retardation, akinesia, loss of purposeful hand use, seizures and respiratory disorders. In 1980, Hagberg (5), unaware of Retfs earlier work, described similar features in 16 Swedish girls. In 1983 (6), he and his associates reported a pooled series of 35 French, Portuguese and Swedish female patients with Rett syndrome (RS). Since that time, awareness and interest in this emerging clinical entity has intensified. With the exception of electroencephalography (EEG), laboratory findings are usually normal and the pathogenesis of RS has remained obscure. However, in 1984, Nomura et al (17) proposed that RS is a developmental monoaminergic deficiency state. On the basis of further clinical observations and polysomnographic studies, Nomura et al (18) and Nomura and Segawa (19) speculated that RS symptomatology results from a disorder of the noradrenergic, serotonergic and dopaminergic systems arising respectively, in the locus ceruleus, raphe nucleus and substantia nigra. In 1985, Zoghbi et al (25) reported significantly reduced levels of 3-metho~y-4-hydroxy-phenylethylene glycol (MHPG), a metabohte of norepinephrine (NE), and homovanilic acid (HVA),a metabolite of dopamine (DA), in the cerebrospinal fluid (CSF) of six RS children. CSF levels ofthe serotonin (5HT) metabolite, 5-hydroxyindoleacetic acid (HIAA), have been reported variously as reduced (4, 20) or unchanged (1, 8, 25). There is no apparent disturbance of peripheral biogenic amine function. Adrenomedullary catecholamine production and synthesis of biogenic amines in other peripheral organs and nerves is unaffected (22). Results of post-mortem brain studies are variable and unrevealing except for the consistent finding of reduced melanin content in the neurons of the substantia nigra (10,12).

R. Pelligra et al

dos a diferentes intervalos, revelaron un inmediato y marcado aumento en la producci6n de aminas biogenicas en el sistema nervioso central. EI aumento de la producci6n de aminas biogenicas asociada a una mejorfa de la sintomatologia clfnica sugiere una correlaci6n entre ambos hechos y provee fundamenta adicional para un papel etiol6gico de la disfunci6n de neurotransmisores en el sindrome de Rett. En un estudio complementario se observ6 que el aumento de CO 2 pulmonar luego de la aplicaci6n de un respirador simple produjo mejorfa en los niveles de gases sangufneos y eliminaci6n deI ritmo respiratorio tipo CheyneStokes observado en sindrome de Rett. Se observ6 ademas una casi normalizaci6n deI electroencefalograma luego de la restauraci6n de un ritmo respiratorio normal artificialmente inducido. Los resultados enunciados conducen a la conclusi6n preliminar que la hipoxemia cerebral secundaria a una funci6n respiratoria anormal, puede contribuir a la disminuci6n en la producci6n de aminas biogenicas en el sindrome de Rett.

Although breathing irregularities are considered a main clinical characteristic of RS (7, 13), their relationship to the underlying pathophysiological process is not known. Our own observations indicate that the RS breathing pattern, which is characterized by irregular cycles of hyperventilation alternating with periods of apnea, is strikingly similar to the Cheyne-Stokes breathing seen at high altitude. Hypoxia due to reduced partial pressures of oxygen at altitude leads to cycles of hyperventilation followed by hypocapnia induced apnea (11). On the basis of these observations, we attempted to examine a possible causal relationship between respiratory abnormalities and neurotransmitter (NT) dysfunction in RS children. In the preliminary studies, we observed that altering pulmonary function resulted in both subjective and objective improvements. Blood gases and respiration improved with the use of a simple rebreathing device that causes an increase in pulmonary CO 2 . Near normalization of the EEG occurred when a regular breathing pattern was imposed by means of arespirator. We attempted, therefore, to induce a more intense and sustained hypercapnic hyperoxemia in two RS children by having them breathe an 80 % O2 / 20 % CO gas mixture. The presumption was that the elevated CO2 would prevent the apnea and that the combined effects of vasodilation and enriched O2 would result in marked cerebral perfusion and hyperoxemia. The effect of this respiratory intervention on plasma NT and NT metabolites was determined before, during and after inhalation of the gas mixture. Thus, the subjects served as their own pre-exposure controls. CSF sampling was excluded for ethical reasons.

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132

Rett Syndrome: Stimulation ofEndogenous Biogenie Amines

Case 1

Following an apparently normal pre- and perinatal period, Case 1 began a rapid deterioration of her development, growth and behavior beginning at about 10 1/2 months of age. Whereas she had begun to walk at 8 months and say words at about 9 months, by 2 years of age she had become speechless and had developed an ataxie gait, purposeless clapping/wringing motions of the hands, and autistic behavioral characteristics. She was first seen by us at age 6 years, 5 months. At that time she was experiencing seizures in addition to the previously mentioned symptoms. Case2

This patient was diagnosed as having RS at age 9. Her parents became aware that there was a problem when she was 15 months old. She subsequently d~veloped an ataxie gait, purposeless handwringing motions, seizures and evidence of autistic behavior and mental retardation. Beginning at age 10, she was periodically exposed to transient hypercapnic hyperoxemia in our laboratory. Prior to initiation of this experimental regimen, both sets of parents were informed of the possible inconveniences, discomforts and risks to their child.

Methods In both patients, transient hypercapnic hyperoxemia was induced by administering a mixture of 80 % 02 and 20 % CO 2 medical grade gas using a 100 % demand regulator and an oral/nasal mask. Because of periodic apneic episodes in the typical respiratory pattern of these children, timing of the administration period was begun at the first inspiration foIlowing mask emplacement. Voluntary respiration continued with this gaseous mixture for a 30 second duration at which time the mask was removed and the patient resumed breathing ambient air. Direct arterial P0 2 and PC0 2 values were obtained in Case 1 on one occasion. Subsequent measurements were made utilizing non-invasive techniques. These included analysis of end expiratory breath sampies by mass spectrometry and transcutaneous measurements of "arteriolized" capillary blood. Transcutaneous 02 (Ptc0 2) and CO 2 (PtcC0 2) values were obtained with the use of transcutaneous sensors (Novametrix Medical Systems, Inc.). The sensors were calibrated and placed on the patient's anterior ehest wall at the midclavicular line approximately 2 cm below the left clavicle. An indwelling catheter was placed in an antecubital vein to allow serial sampling of blood for evaluation of qualitative and quantitative time course changes in NT activity. Sampies were retrieved at 30 and 15 minutes (min) prior to administration of the gaseous mixture, immediately following, and at 15, 30 and 60 minutes post exposure. Plasma was separated and quick frozen in dry ice. Analysis of sampies for NTs and their metabolites was performed by utilizing n-electrode three dimensionalliquid chromatography (n-ELC) with electrochemical detection to assay a number of NTs and their metabolites that are

133

released into the plasma. This methodology was developed at ESA Laboratories, Bedford, MA. by Matson et al (14). Metabolite ratios derived from these data are used to ascertain the relative contributions of somatic or central NT activity to the overall level of plasma metabolites. In brief, analysis of the biochemical data is based on the following established relationships (2): In the CNS, the primary noradrenergic metabolite is MHPG, whereas peripheral processes lead to VMA. The primary dopaminergic system metabolites in the CNS are dihydroxyphenyl acetic acid (DOPAC) and HVA; peripheral DA metabolizes through 3-methoxy tyramine (3MT) and MHPG and peripheral L-dopa (LD) metabolizes through 3-0-Methyl Dopa (OMD) and 4-hydroxy-3-methoxyphenyllactic acid (4,3-HMPLA). The 3-Methoxy-4-Hydroxy Phenyl Ethanol (MHPE) is used as an indicator of peripheral DA metabolism. For the rebreathing studies, a mask with a 750 ml rebreathing bag and a 3 mm port to ambient air was placed over the patient's nose and mouth. During the test period, respiratory and cardiopulmonary parameters were also monitored. Results Inducing a transient state of hypercapnic hyperoxemia by inhalation of a gaseous mixture of 80 % 02 / 20 % CO 2 had an immediate and profound effect on CNS biogenie amine levels and metabolism. This is indicated by the results from Patient 1 shown in Table 1. The data presented fit the pattern of a stimulation of CNS dopaminergic turnover through LD to DA, DOPAC, and HVA with a very small peripheral contribution. The total increase of HVA and DOPAC vs. MHPE and 3MT is by a factor of approximately 14: 1 (8400 pg/ ml vs. 620 pg/ml). This latter value is comparable to the sum of the DA spike values observed (490 pg/ml) and presumably refleets these increases. The precursor LD does not change significantly in the plasma, nor do its peripheral metabolites OMD and 4,3-HMPLA. The initial spikes in NE and epinephrine (E) are consistent with a stress response to the insertion of the sampling device. This is reflected in the increase in the peripheral metabolite, VMA. Although there is no significant change in free MHPG, the MHPG sulfate increases substantially post treatment. In combination with the strong indication of CNS DA turnover mentioned above, this implies a similar increase in CNS NE turnover, leading to MHPG which is rapidly sulfated. The data from Case 1 cannot be compared directly to the data from Case 2 (Table 1) because the sampling periods and pre-exposure conditions were significantly different. Nevertheless, the data from Case 1 also showed a remarkable 15 min post-exposure increase in HVA with values increasing from 4585 pg/ml baseline to 7512 pg/ml. This was followed by a large peak of DOPAC (from 375 pg/ml to 904 pg/ml) as weIl as lesser peaks of LD (1457 pg/ml to 2569 pg/ml) and DA (267pg/ml to 714 pg/ml), indicating a marked increase in turnover of CNS DA. As with Patient 2, MHPG was rather stable. In Case 1, however, MHPG-S0 4 values were not obtained and therefore we do not have this indicator of increased noradrenergic activity. However, there was a three-fold increase (from 2844 pg/ml baseline to 9641 pg/ml) in the post-exposure normetanephrine output. This is consistent with increased CNS noradrenergic activity.

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Patients and methods

Neuropediatrics 23 (1992)

R. Pelligra et al

134 Neuropediatrics 23 (1992)

Table 1 Plasma biogenic amines and metabolites following inhalation of an 02/C02 gas mixture. Blood sampies were obtained via an indwelling intravenous catheter at 30 and 15 min prior to a 30-second inhalation of an 80 % 2 /20 % CO 2 gas mixture and immediately, 15, 30 and 60 min after.

°

Min Norepinephrine Epinephrine Dopamine L-Dopa 3-0-Methyl Dopa 4-Hydroxy-3-Methoxy Phenyl Lactic Acid 3-Methoxy Tyramine Dihydroxy Phenyl Acetic Acid Homovanillic Acid 3-Methoxy-4-Hydroxy Phenyl Ethanol Vanillyl Mandelic Acid 3-Methoxy-4-Hydroxy Phenyl Glycol MHPG Sulfate Conjugate

I NE E DA LD 30MD 4,3-HMLPA 3MT DOPAC HVA MHPE VMA MHPG MHPG-S04

I

POS~ 1

+ 15

+ 30

+ 60

162 45 0 1680 390

425 280 160 1590 395

280 130 0 1 710 430

240 115 60 1565 440

240 45 0 1620 420

120 420 2840 11200

135 360 2660 11300

110 360 2690 10900

130 420 2920 11300

160 580 3760 12200

120 620 4120 18300

1100 2800

990 3440

1010 3910

1200 4120

1620 3620

1520 3590

4100 36000

3980 37000

3910 36100

3810 37500

3910 42100

3870 42 100

pr~ 30

- 15

520 1100 310 1635 420

I

Note: Units are picograms per milliliter of plasma

Figure 1 shows the baseline respiratory patterns and cardiovascular parameters for Case 1. Case 2 was similar. As indicated, our patients displayed the typical RS respiratory pattern described previously as "episodic hyperpnea". Of particular interest were the low baseline values of end expiratory CO 2 (1.8 %) and high 02 (18 %). CO 2 and 02 end expiratory determinations in anormal, age/sex matched control were 6 % and 15 % respectively. Resting arterial blood gases measured subsequently in Case 1 revealed a PC0 2 of 25 torr and a P0 2 of 120 torr. Resting PtcC0 2 (transcutaneous)

values as low as 16 torr were measured in Case 2 and average PtcC0 2 and Ptc0 2 values were compared to measurements taken in eight female and five male, normal children. In 13 subject determinations, the mean level (± SD) of PtcC0 2 was 23.6 ± 2.6 torr compared to control values of 37 ± 2.7 torr (p < 0.001). Ptc0 2 values were 91.2 ± 5.2 torr compared to control values of 76.5 ± 2.5 torr (p < 0.05). In our studies using a rebreathing mask, the effects of rebreathing expired air on the above parameters were

105

j

.: 95 % 85

]200 ]:00 BPM

Fig. 1 Typical Rett Syndrome respiratory pattern, blood and heart rate changes during rest (Case 1). Alternating periods of apnea and hyperpnea (HYP) (eheyne-Stokes) associated with changes in 02 saturation, heart

rate, ECG and temporal artery blood flow as measured by transcutaneous Doppler ultrasan ic flowmeter.

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Inhalation

Rett Syndrome: Stimulation ofEndogenous Biogenie Amines

Neuropediatrics 23 (1992)

135

Rebreathing and respiratory patterns in Rett Syndrome (Case 1). Cheyne-Stokestype breathing was largely eliminated after about 2 1/2 min-

Fig. 2

followed. The results are shown in Figure 2. The C0 2 levels rose to a maximum of 3.6 % and 02 fell to a minimum of 12.5 % at the end of 2.5 min and persisted unchanged until the mask was removed at 5 min. However, during this same period, respirations became deep and regular, the hyperpnea/apnea pattern was eliminated, heart rate stabilized and the patient became calm and relaxed. The hyperpnea/apnea pattern was also overcome or overridden by the mechanical imposition of a regular respiratory pattern. When a regular breathing pattern was imposed on the same patient by utilizing a positive pressure respirator device, near normalization of a diffusely abnormal EEG occurred (Figure 3). After 30-60 seconds, the EEG tracing decreased in voltage and no further spikes were present. There was a significant decrease in the number of slow delta waves. Ten to fifteen second periods of what appeared to be an almost normal EEG recording with beta activity were noted. The results of clinical intervention in the RS are difficult to assess because objective criteria cannot be assigned to the observed changes in symptomatology. The one feature that is distinctive of RS, if not pathognomonic, is the perseverative handwringing motion that is difficult to describe but unmistakable on viewing. In Case 2, this seemingly purposeless hand action had diminished by at least 50 percent according to conservative estimates of her physicians, therapists, and parents. For the first time, the child began to respond to her environment with quizical interest and turned towards the caller when her name was spoken. Seizure episodes decreased in frequency, intensity and duration. The patient made more frequent and determined efforts to ambulate, but was restrained by orthopedic deformities. She began to demonstrate increasing control over micturition.

utes of rebreathing into a semi-c1osed system wh ich allowed the CO 2 level to increase. Percent of expired 02 and CO 2 scales are inverted.

Discussion

The criticality of 02 for virtually every brain function is so obvious and well-established that 02 deprivation as a contributing cause of CNS dysfunction is perhaps easily overlooked in the search for etiological factors. An important finding of this preliminary investigation is the apparent direct and immediate link between respiratory function and some of the biochemical and clinical manifestations of RS. The results suggest that chronic cerebral hypoxia resulting from abnormal respiratory function may contribute to impaired biogenic amine production in RS. The findings, although compelling, are indirect and must be considered preliminary in view of the limited number of subjects and the lack of age/sex-matched contro!. Direct CSF measurements by lumbar puncture and the use of normal children as controls could not be ethically justified. However, by comparing pre- and post-exposure responses in this presumed deficiency state, we were able to use our subjects as their own controls. Following intervention, they demonstrated increased levels of amines above deficient steady state values. Breathing irregularities are considered a main clinical characteristic of RS (7, 13). Hagberg et al (6) reported "episodic hyperpnea" in 23 of their 35 cases, and Lugaresi et al (13) suggested, on the basis of their clinical experience, that breathing disturbances may be present at some stage in every case of RS. The breathing pattern is characterized by irregular cycles of hyperventilation alternating with periods of apnea which, in some patients, may last as long as 120 seconds with marked reduction in arterial oxygen saturation, cyanosis, and unconsciousness (13). Subnormal oxygen pressures or a circulatory deficiency induced experimentally in normal waking subjects produces Cheyne-Stokes breathing which is strikingly similar to

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AP=APNEA HVP =: HYPERPNEA

Neuropediatrics 23 (1992)

R. Pelligra et al

,f, DURfNG ANO 2

min POST RESPIRATOR

t 105

1,,·::96 :% ]85 ]200

J:

OO

BPM

Fig. 3 Effect of respirator-induced breathing pattern on EEG (Case 2). Left side of figure shows typical alternating apnea and hyperpnea and the

corresponding EEG. Right side of figure shows the effect of mechanically maintained, regular respiration on EEG.

the periodic breathing pattern of RS (3). The apnea associated with Cheyne-Stokes breathing of high altitude is known to be related to both hypoxia and hypocapnic alkalosis and is also eliminated by the inhalation of CO 2 (11).

thereby simultaneously increasing 02 demand while decreasing 02 supply.

It cannot be determined from our data whether the Cheyne-Stokes-like pattern of RS is induced by hypoxia or hypocapnia. Either could result from CNS dysfunction due to, for example, intrinsic mitochondrial or metabolie disease or an inadequate supply of 02 to the brain stern. Philappart (21) has, in fact, proposed that RS is a generalized disorder of energy metabolism. This is based on his findings of lactic and pyruvic acidosis and ultrastructural abnormalities of mitochondria in brain and liver. The evidence for hypocapnia in our cases sterns from three sourees: the abnormally low resting PaC0 2 and PtcC0 2 values; the salutary effects of rebreathing expired air on depth and regularity of respiration, heart rate and behavior (Fig.2); and the near normalization of a diffusely abnormal EEG when the pattern of episodic hyperpnea was obliterated by means of a positive pressure respirator (Fig. 3). Hypocapnia is known to cause a selective reduction in cerebral blood flow and, by the Bohr effect, shifts the oxyhemoglobin curve to the left. This pH-mediated shift results in an increased affinity of hemoglobin for 02 with further deprivation of 02 at the brain tissue level. Furthermore, the degree of hypocapnia seen in our patients (20 torr range) has been shown to increase intracerebral 02 consumption up to 100 % (15),

These factors could, in combination, lead to severe cerebral hypoxia or dysoxia. The term dysoxia, introduced by Robin (24) in 1977, refers to abnormal tissue oxygen metabolism that results from disturbances of either oxygen transport or oxygen utilization. Dysoxia may be present despite normal hematological.and cardiopulmonary functional parameters. Dysoxia is known to cause a reduction of the in vivo synthesis of 5HT, NE and DA without necessarily affecting neuronal energy metabolism, axonal conduction, or release of monoamines (9). It is possible that the hyperoxemia induced experimentally in our patients may have temporarily relieved an underlying, chronic dysoxia that restriets the rate-limiting, oxygen dependent (16), conversion of tyrosine to DA and NE (Fig.4). Although NT metabolism can only account for a small portion of the total 02 consumed by the brain, it is, as indicated above, a process that can be more vulnerable to 02 deprivation. The observations that stereotypie signs and symptoms of RS are exacerbated by increased effort and relieved during REM and NREM sleep (13) could be explained by the more sensitive response of NT synthesis to the marginal availability of 02' During sleep, brain 02 consumption remains essentially unchanged, but cerebral blood flow increases, resulting in a net increase in the amount of 02 supplied to brain tissue.

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136

Neuropediatrics 23 (1992)

Rett Syndrome: Stimulation ofEndogenous Biogenic Amines OH

HO-Q-Y-f-NH

I

L-TYROSINE

Fig. 4

Synthetic pathway for conversion of L-Tyrosine to Dopamine and Norepinephrine. The conversion of L-Tyrosine to L-Dopa is ratelimiting and critically dependent on the presence of 02'

OH

HO

I

I

-0 I I

I

1

~!J -C-C-NH 2

DOPAMINE

I

1t is of interest that in the autopsy studies of eight RS cases reported by Jellinger and Seitelberger (10) and subsequently confirmed by Lekman et al (12), no pathological changes were seen in the locus ceruleus or in the substantia nigra, except for hypopigmentation in the latter nucleus. Neuromelanin in the substantia nigra iso a polymer of DA or its metabolites, and the degree of pigmentation in these neurons is correlated with the amount of DA they contain. These findings are consistent with a functional disorder of NT synthesis rather than of abnormalities in the structure or number of intrinsic neurons. Our results also imply that although NT production is deficient, synthetic pathways in RS appear to be intact and responsive. Perhaps the underlying functional abnormality is a chronic or episodic insufficiency of oxygen at critical sites in the brainstem. Additional studies are needed to determine whether focal cerebral dysoxia can account for NT abnormalities in RS and similar childhood brain disorders. Rapid developments in non-invasive techniques such as positron emission tomography and nuclear magnetic resonance imaging may provide new clues as to the role of 02 utilization, blood flow, or other dynamic dysfunctional states in the pathogenesis of RS. Acknowledgments We are indebted to Erie Doman and Ivor Burgessor for their assistance in data acquisition and handling; to Drs. Alan Sossin and Robert Loudin for blood sampIe retrieval and preparation; and to Margie Glazer and Zoila Neves for manuscript preparation and editing. Special thanks to Ann Ball for supervising patient care and the administration of inhalation therapy.

References 1 2

3 4 5

6

Budden, S. S.: Rett syndrome; studies of 13 affected girls. Am. J. Med. Genet. 24 (Suppl. 1) (1986) 99-109 Davis, B. A.: Biogenie amines and their metabolites in body fluids for normal, psychiatrie and neurological subjects. J. Chromatogr. 446 (1989) 89-218 Douglas, C. G., J. S. Haldane: The causes of periodic or Cheyne-Stokes breathing. J. Physiol. (London) 38 (1909) 401-419 El-Hibri, H. Y., A. K. Percy, 1.J. Butler: Biogenie amine metabolism in Retfs syndrome. Neurology 35 (Suppl. 1) (1985) 198 Hagberg, B.: Infantile autistic dementia and loss of hand use: areport of 16 Swedish girl patients. Presented at the research session of the European Federation of Child Neurology Societies, Manchester, England, June 1980 Hagberg, B., J. Aicardi, K. Dias, O. Ramos: A progressive syndrome of

HO TYROSINE HYDROXYLASE

I

COOH

11 ~ ~ -C-C-NH I I

-b

L-DOPA

Cu++,ASCORBATE, O2

•

DOPAMIN E·ß-HYDROXYLASE

PYRIDOXINE-P04 DOPA DECARBOXYLASE

I H 0 II ~ IJ -C-C-NH 2

OH

HO

I

~

I I

L-NOREPINEPHRINE

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