Cataplexy and monoamine oxidase deficiency in Norrie disease

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

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.