Cataplexy and monoamine oxidase deficiency in Norrie disease
Citation Manager Formats
Make Comment
See Comments

Abstract
Norrie disease (ND) is an X-linked recessive disorder causing ocular atrophy, mental retardation, deafness, and dysmorphic features. Virtually absent monoamine oxidase (MAO) type-A and -B activity has been found in some boys with chromosome deletions. We report the coexistence of cataplexy and abnormal REM sleep organization with ND. Three related boys, referred for treatment of medically refractory atonic spells and apneas, underwent extended EEG-video-polysomnographic monitoring. They demonstrated attacks of cataplexy and inappropriate periods of REM sleep during which they were unarousable. One boy also had generalized tonic-clonic seizures. Previous testing revealed that all three have complete ND gene deletions. In all subjects, platelet MAO-B activity was absent, serum serotonin levels were markedly increased, and plasma catecholamine levels were normal. Data from the canine narcolepsy syndrome model implicate abnormal catecholaminergic and cholinergic activities in the pathogenesis of cataplexy. Our findings suggest that abnormal MA0 activity or an imbalance between serotonin and other neurotransmitter levels may be involved in the pathogenesis of human cataplexy.
Norrie disease (ND, McKusick #31060) is a rare disorder characterized by infantile blindness, pseudotumorous retinal dysgenesis, ocular atrophy, and other signs. 1–3 It is associated commonly with mental retardation, sensorineural deafness and dysmorphic features, and occasionally with atonic seizures. 1–4 We studied three boys with ND and found them to have cataplexy and abnormal REM sleep with no other signs of narcolepsy. To our knowledge, this is the first report of this association. In addition, we found marked alterations of their serum serotonin (5HT) and platelet monoamine oxidase type-B (MAO-B) levels. These observations suggest possible mechanisms for cataplexy in humans.
Methods
Two brothers and a male maternal cousin with ND were referred with diagnoses of medically refractory atonic seizures and apneic spells. Combined 24-hour EEG-video-polysomnographic monitoring was carried out for 2 to 6 days. EEG, EMG, eye movements, pulse oximetry, thoracic movements, airflow, ECG, and video were digitally recorded in these three children using methods described previously. 5 A 32-year-old man with ND, who is the maternal uncle of these children, was not monitored but is described by his sisters to suffer from episodes of muscular atonia and generalized tonic-clonic seizures. All four affected males and the mothers of the children are known to have a submicroscopic deletion of the entire ND gene (Maumanee, Johns Hopkins University, Baltimore, MD, personal communication). Serum 5HT was assayed using high-pressure liquid chromatography (HPLC) and compared with laboratory normative data for 40 healthy adults and literature 6 norms for children (Specialty Laboratories, Inc., Santa Monica, CA). Blood was drawn for catecholamine levels in fasting nonmedicated subjects after at least 30 minutes of rest. Plasma norepinephrine (NE), dopamine (DA), and epinephrine (E) levels were as-sayed 7 using HPLC with electrochemical detection after a two-step chromatographic purification (Mayo Clinic Laboratories, Rochester, MN). MAO-B activity was assayed 8 from platelet-rich plasma prepared from venous blood collected in EDTA by differential centrifugation. MAO-B normative data were from a published study 9 of 680 healthy adults.
Case Reports
Patient 1
At age 2 months, this boy developed ocular signs of ND and began having “seizures” characterized by an arrest of motion and minimal variable trembling or clonic movements. A head CT was normal. By age 6 months, episodes developed in which he became suddenly limp an average of 10 times daily. He was treated with phenobarbital (PB) and carbamazepine (CBZ) with no benefit. Three EEGs between ages 9 and 27 months revealed mild diffuse nonepileptiform abnormalities. At age 31 months, parents noted seizures characterized by sudden loss of body tone with upward eye deviation occurring up to 100 times daily, hypothermic episodes, and abnormal sleep patterns manifested by wakefulness for days at a time and, alternatively, being completely unarousable from sleep. He occasionally was given chloral hydrate to induce sleep. During long-term EEG-video-polygraphic monitoring at age 31 months, he had a 7-second episode of cataplexy associated with EEG patterns similar to wakefulness in this child and two periods of REM sleep from which he could not be aroused for up to 12 minutes despite vigorous tactile and loud auditory stimulation. A subsequent trial of imipramine 25 mg twice daily produced tachycardia and irritability but had no' effect on his cataplexy. A trial of divalproex sodium (VPA) produced pain that triggered cataplectic attacks.
At age 4.25 years his mother reported that cataplexy (reliably triggered by pain or laughter from being tickled) and excessively long periods of sleep in which he was limp and unarousable continued with unchanged frequency. Repeat EEG-video monitoring recorded multiple attacks of sudden muscle atonia associated with waking EEG patterns. We could not test his level of consciousness or deep tendon reflexes during these episodes because of both his mental retardation and the 4- to 8-second duration of the episodes. Platelet MAO-B and serum 5HT levels were markedly abnormal, but plasma NE, DA, and E levels were normal (table). Venous plasma ammonia was 60 pmon (normal, 9 to 331, but alanine, glutamine, and ornithine levels were normal. Later, during a 5-week period, he slept only a few nights, had lengthy daytime naps associated with myoclonic activity and REM sleep from which he could not be aroused, and had innumerable daily cataplectic attacks. Cyproheptadine was tried beginning at 1 mg qd and then increasing at 1 mg increments to 2 mg every morning and 1 mg every afternoon. After each dose increase, he consistently experienced a transient increase in diurnal sleepiness lasting 1 week. While chronically taking 3 mg qd, his sleep patterns almost completely normalzed and the cataplectic spells decreased to 0 to 10 a day. He also was able for the first time to rise to a sitting position by himself and had a much longer attention span.
Table. MAO-B and neurotransmitter levels in patients and their mothers
Patient 2
The younger brother of patient 1 developed episodes in which he became suddenly limp, apneic, and unresponsive at age 4 months. He was treated with PB, and later with CBZ and phenytoin, without improvement. At age 6 months, these spells were occurring three times daily. He underwent EEG-video-polysomnographic monitoring during which two attacks of muscle atonia and apparent REM sleep beginning suddenly during wakefulness were recorded. Subsequently, he was not treated with medications. At age 23 months, he rarely had cataplexy, but he continued to have daily spells of sleep from which he could not be aroused for 30 to 60 minutes. Abnormal platelet MAO-B and serum 5HT and normal plasma NE, DA, and E levels were found in this boy and his mother (table). Venous plasma ammonia was 53 pmol/L (normal, 9 to 331, and alanine, glutamine, and ornithine levels were normal.
Patient 3
The cousin of patients 1 and 2 was also studied because of spells occurring twice daily. At age 15 months, he began having attacks of sudden muscular atonia with falls triggered by illness, laughter, or anger. An EEG revealed mild background nonepileptiform abnormalities. Medications included PB and diazepam. Subsequent EEG and head CT were normal. At age 7 years, EEG-video-polysomnographic monitoring recorded two episodes of cataplexy with brief apnea lasting 11 to 17 seconds and two independent generalized tonic-clonic seizures with diffuse ictal EEG discharges. Interictally, diffuse 1.5- to 2-Hz sharp-and-slow-wave patterns were recorded. Subsequent trials of WA produced vomiting and edema, and CBZ produced irritability, anorexia, and weight loss, so PB was continued. His parents then reported abnormal sleep patterns with periods of complete wakefulness and no sleep lasting up to 3 days and frequent attacks of cataplexy that could be triggered by startle, emotion, pain, or laughter. Platelet MAO-B and serum 5HT levels were markedly abnormal in this boy and moderately abnormal in his mother (table). Cyproheptadine 5 mglday made his nocturnal sleep nearly normal for 6 weeks, but it was stopped because of daytime leg restlessness. Subsequently, his mother observed that avoidance of foods with large amounts of tyramine improved his nocturnal sleep patterns markedly.
Discussion
The ND gene has been mapped to the proximal short arm of the X chromosome (Xp11.31, centromeric to the MAO-A and -B genes 1,8,10 that, in turn, are centromeric to the DXS7 locus. 11 A variety of chromosomal abnormalities including deletions, inversions, and point mutations occur and may be responsible for the varied clinical manifestations. 1,3,8 The ND gene encodes a protein of 133 amino acids with some homologies to the C-terminal group of proteins, such as mucins. 4,10 An altered protein has been found in the CSF of ND patients with deletions. 3
In males with ND deletions, evidence of virtually absent plasma MAO-A and -B but normal plasma amine oxidase activities have been noted. 8,12 In addition, normal plasma and moderately elevated CSF NE and markedly increased plasma and CSF 5HT levels have been observed. 8,12 5-Hydroxyindoleacetic acid (5HIAA), produced by deamination of 5HT by MAO-A, is markedly decreased in CSF. 8,12 Methoxy-hydroxyphenylglycol (MHPG), produced by deamination of NE by MAO-A, is markedly decreased in plasma and urine. 8,12 In one male with an ND deletion, there was a 60-fold increased sensitivity to tyramine. 12 Patients without deletions may not have abnormal MAO-A or -B activities. 13
To our knowledge, the association of ND with cataplexy and abnormal REM sleep organization has not been previously reported. ND patients said to have atonic seizures 4,13 and a boy with ND whose mother observed “a few brief atonic ‘spells’ preceded by a period of agitation, usually in response to a loud noise” 12 may actually have had cataplexy. One study 13 mentioned “sleep disturbance” among a list of signs exhibited by two patients. Cataplexy occurs rarely in young children. Despite this, and although we could not assess cognition or tendon reflexes during our patients' brief attacks, we believe that the recorded episodes were cataplectic based on their clinical features with concomitant waking EEG patterns, the association with abnormalities of REM sleep, and the parents' observations that the spells are triggered by emotion in all three children.
Cataplexy is one sign associated with the narcolepsy syndrome, a disorder of REM sleep organization and timing. Evidence for the roles of altered NE, DA, 5HT, and acetylcholine (ACh) function has been derived from canine narcolepsy models and from investigations with pharmacologic agents that affect these transmitters or their receptors. 14–18 In our patients, we found absent platelet MAO-B activity and elevated serum 5HT but normal NE, DA, and E plasma levels. These findings are consistent with the decreased MAO-A and -B activities seen in other boys with ND deletions. 8,12 It is assumed the deletion involves the MAO-A and -B genes as well as the nearby ND gene.
We propose three possible mechanisms for cataplexy and REM sleep disturbance in our ND patients. First, the absence of MAO activity in these patients may be only indirectly involved in the pathogenesis of cataplexy through elevation of 5HT levels relative to other neurotransmitter levels. Second, despite the high 5HT serum levels, hypoactivity of serotonergic systems (because of a congenital absence of MAO) may cause the cataplexy/REM disorder in ND. Third, the altered or absent ND gene product, or the missing product of other deleted genes contiguous with the ND gene, may be responsible for our observations.
Regarding the first explanation, an indirect mechanism for the absence of MAO is postulated because MAO inhibitors are effective in the treatment of cataplexy. 14 As suggested by the observations that central muscarinic cholinergic agonists and alpha-1b NE postsynaptic receptor antagonists exacerbate and alpha-1b NE agonists and alpha-2 NE and D2 DA presynaptic receptor antagonists suppress canine cataplexy, 14,16,17 an imbalance between high 5HT and normal NE, DA, or ACh activity could account for cataplexy and REM sleep disturbance in ND. In support of this mechanism is the observation that cypro-heptadine, a serotonin antagonist, normalized sleep patterns in patients 1 and 3. Cyproheptadine has been used to treat the symptoms that occur in patients taking selective serotonin reuptake inhibitors (or other drugs) with MAO inhibitors. l9 A clinical study 20 of the brains of three people with narcolepsy syndrome found elevated 5HT levels but normal NE and DA levels in several brain areas on postmortem examination. The latter results may also be consistent with this explanation.
The second mechanism, namely that cataplexy in ND is due to chronic 5HT neuronal hypoactivity, is supported by a recent report. 21 In that study, rats were administered MAO inhibitors during pregnancy and the pups' brains were examined postnatally. Significant reductions of 5HT neuronal density were found, particularly in pups given MAO inhibitors after birth and until they were killed. This is interesting in light of the observations that during REM sleep, the firing rates of 5HT neurons in the dorsal raphe and NE neurons in the locus coeruleus dramatically decrease, whereas the activity of ACh neurons increase. l5 This second mechanism is consistent with the accumulated results of work with the canine narcolepsy model that suggests a widespread hyperactivity of cholinergic systems in the brain together with global hypoactivity of catecholaminergic systems underlie the pathophysiology of narco-lepcy. l5 It has been shown that presynaptic activation of the NE system, but not of the DA or 5HT systems, is the main regulator of canine narcolepsy. 15 This explanation may also be in keeping with the finding in canine narcolepsy that 5HT-1A receptor agonists suppress cataplexy. 22
We cannot rule out the third possibility, that deletion of the ND or other contiguous genes directly causes the observations we report here. One example of another contiguous gene is an ornithine amino-transferase (OAT)-like sequence located centromeric to the ND gene (Xp11.21-11.22). 11 However, the urea cycle metabolite plasma levels in patients 1 and 2 provide no evidence to suggest deficiencies of OAT.
Based on the preliminary observations reported here, it appears that the congenital absence of MAO in our ND patients is indirectly responsible for their cataplexy and REM sleep disturbance. This may be due to either the high 5HT levels or low 5HT neuronal density (or both) relative to other neurotransmitter activities. Additional studies may be warranted on the roles of aberrant MAO, 5HT, ACh, and cate-cholamine activities in human cataplexy.
Acknowledgments
We thank Dr. Irene H. Maumanee, Johns Hopkins University, for providing the results of the genetic studies on these individuals; Dr. Dennis L. Murphy, National Institutes of Health, for information on MAO assays; and Drs. Bernie Brown, Poulsbo, Washington, and John P. Ries, Coos Bay, Oregon, for patient follow-up information.
Footnotes
-
Supported by the Epilepsy Center Foundation. Swedish Health Services, Seattle, Washington.
Presented in part at the 47th annual meeting of the American Academy of Neurology, Seattle, WA, 1995.
Received September 18, 1995 Accepted in final form October 30, 1995.
- Copyright 1996 by the American Academy of Neurology
References
- 1.↵
Wong F, Goldberg MF, Hao Y. Identification of a nonsense mutation at codon 128 of the Norrie's disease gene in a male infant. Arch Ophthal 1993;111:1553–1557.
- 2.
- 3.↵
Joy JE, Poglod R, Murphy DL, et al. Abnormal protein in the cerebrospinal fluid of patients with a submicroscopic X-chromosomal deletion associated with Norrie disease: preliminary report. Appl Theo Electrophor 1991;2:3–5.
- 4.↵
Chen Z-Y, Hendriks RW, Jobling MA, et al. Isolation and characterization of a candidate gene for Norrie disease. Nature Genet 1992;1:204–208.
- 5.↵
- 6.↵
- 7.↵
Sheps SG, Jiang N, Klee GG. Diagnostic evaluation of pheochromocytoma. Endocrinol Metab Clin North Am 1988;17: 397–414.
- 8.↵
- 9.↵
Murphy DL, Wright C, Buchshaum M, Nichols A, Costa JL, Wyatt RJ. Platelet and plasma amine oxidase activity in 680 normals: sex and age differences and stability over time. Biochem Med 1976;16:254–265.
- 10.
- 11.↵
Bateman JB, Kojis TL, Cantor RM, et al. Linkage analysis of Norrie disease with an X-chromosomal ornithine aminotransferase locus. Trans Am Ophthalmol SOC 1993;9:299–308.
- 12.↵
- 13.↵
- 14.↵
Guilleminault C. Narcolepsy syndrome. In: Kryger MH, Roth T, Dement WC, eds. Principles and practice of sleep medicine. 2nd ed. Philadelphia: WB Saunders, 1994:549–561.
- 15.↵
Nishino S, Reid MS, Dement WC, Mignot E. Neuropharmacology and neurochemistry of canine narcolepsy. Sleep 1994;17:S84–S92.
- 16.
Nishino S, Fruhstorfer B, Arrigoni J, Guilleminault C, Dement WC, Mignot E. Further characterization of the alpha-1 receptor subtype involved in the control of cataplexy in canine narcolepsy. J Pharmacol Exp Ther 1993;264:1079–1084.
- 17.
Boivin DB, Montplaisir J, Petit D, Lambert C, Lubin S. Effects of modafinil on symptomatology of human narcolepsy. Clin Neuropharmacol 1993;16:46–53.
- 18.
Aldrich MS, Hollingsworth Z, Penney JB. Autoradiographic studies of post-mortem human narcoleptic brain. Neuro-physiol Clin 1993;23:35–45.
- 19.↵
Bodner RA, Lynch T, Lewis L, Kahn D. Serotonin syndrome. Neurology 1995;45:219–223.
- 20.↵
Kish SJ, Mamelak M, Slimovitch C, et al. Brain neurotransmitter changes in human narcolepsy. Neurology 1992;42:229–234.
- 21.↵
- 22.↵
Nishino S, Shelton J, Renaud A, Dement WC, Mignot E. Effect of 5-HTlA receptor agonists and antagonists on canine cataplexy. J Pharmacol Exp Ther 1995;272:1170–1175.
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Dr. Nicole Sur and Dr. Mausaminben Hathidara
► Watch
Related Articles
- No related articles found.
Alert Me
Recommended articles
-
Articles
Does monoamine oxidase type B play a role in dopaminergic nerve cell death in Parkinson's disease?Philippe Damier, Anne Kastner, Yves Agid et al.Neurology, May 01, 1996 -
Resident & Fellow Section
Teaching NeuroImages: Sleep-onset REM period during routine EEGKarl A. Kasischke, Amanda Pennington, Selim R. Benbadis et al.Neurology, September 09, 2019 -
Articles
Role of selegiline in combination therapy of Parkinson's diseaseV. V. Myllyla, K. Sotaniemi, O. Maki-Ikola et al.Neurology, December 01, 1996 -
Views & Reviews
Update on the pharmacology of REM sleep behavior disorderJean-François Gagnon, Ronald B. Postuma, Jacques Montplaisir et al.Neurology, September 11, 2006