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Norrie disease (or Norrie-Warburg syndrome) is a rare X linked disorder characterised by congenital blindness due to retinal hypoplasia. A third of patients may additionally have deafness and/or mental subnormality.1 The gene has been mapped to Xp11.4-p11.3, in close proximity to the monoamine oxidase A and B (MAO-A and MAO-B) loci.2
We report a possibly unique case of Norrie disease in a man who described paroxysmal attacks of deafness, slurred speech, and somnolence from his late teens. The character of the attacks, in addition to their marked response to β blockade, argue for the enlargement of the phenotypic character of the disease to include migrainous aura affecting the brain stem.
A 38 year old left handed male computer consultant with Norrie disease sought neurological attention because of episodes of being unwell. He was born with no vision and atrophic eyeballs (phthisis bulbi). At the age of 18 he developed hearing loss necessitating hearing aids; after a period of worsening his hearing stabilised. His paroxysmal attacks began at this age, initially at a frequency of once every 4 or 5 months. During the year before neurological consultation, they increased to once every 2 or 3 weeks. They were predictably associated with stress or stress release. An attack typically began with a gradual deterioration (over a few minutes) of balance with further worsening in the hearing in his right ear, associated with a sense of fuzziness in his head. Occasionally he would experience a loud banging noise. The symptoms progressed to slurred speech, drowsiness, and almost complete deafness in the right ear. Observers described him as appearing pale and in discomfort during these episodes. The attacks could be truncated if he took a tablet or two of Praxilene (100 mg naftidrofuryl oxalate) sufficiently rapidly after the onset of symptoms. Otherwise, they would pass off after a few hours sleep. He did not describe a headache at any time; there was a dislike for food during the attacks but no nausea or vomiting.
His medical history otherwise consisted of mild asthma, controlled by occasional bronchodilator inhaler use. He had a nephew with Norrie disease. There was a family history of migraine in his mother.
General physical examination was normal. Neurological examination disclosed an articulate, insightful man with intact higher mental function. Both eyes were prosthetic. There was mild sensorineural hearing loss, worse on the right. The remainder of the neurological examination was unremarkable.
Brain MRI was normal. Further investigation of his monoamine oxidase status (see below) with urinary catecholamine metabolites, whole blood serotonin, and CSF serotonin and dopamine metabolites was unfeasible for logistical reasons.
The time course, circumstances of precipitation, and positive family history suggested an acephalalgic migrainous disturbance. Despite his asthma, prophylaxis with β blockers was initiated (10 mg propranolol twice a day, building up to a long acting preparation (80 mg Inderal LA once daily). On review 6 months later, he reported a marked positive effect, having had only one, relatively mild attack during the period. His asthma remained well controlled on a more regular use of inhalers.
Norrie disease is a member of a family of disorders that result from mutations in genes occupying the proximal portion of the short arm of the X chromosome. The gene is flanked on either side by the MAO-A and MAO-B loci.2 Point mutations in the Norrie gene lead to at least two other distinct clinical syndromes: familial and sporadic exudative retinopathy, and the retinopathy of prematurity.1 More complex genetic defects arising from larger mutations including the Norrie locus have been described. Vossler et al 3 described three boys with Norrie disease and cataplexy with REM sleep disorganisation. All three patients had absent serum MAO-B activity; serum serotonin was increased, and plasma catecholamines were normal. Collinset al 4 reported on a male patient with a mutation spanning all three of the MAO and Norrie disease loci. The patient had severe mental handicap with myoclonus and stereotyped behaviour disorder; serum MAO activity was undetectable. Chen et al 2 drew attention to a family with pure MAO-A deficiency who had the phenotype of low normal intelligence, impulsivity, cardiovascular problems, and altered concentrations of amine metabolites.
To the best of our knowledge, there is no reported association between Norrie disease (and its genetic variants) and migraine. This is perhaps surprising considering what is the currently accepted wisdom on migraine pathophysiology.5 This strongly implicates the serotonin-MAO axis—migraineurs have increased serotonin and diminished MAO platelet activity between attacks. Our patient was not investigated genetically or with serum MAO determination, but we surmise that he harbours at least a partial defect of MAO-A activity (the relevant enzyme for serotonin degradation). This presumably (and perhaps in conjunction with his familial tendency to migraine) is the metabolic basis for his symptoms.
We conclude that patients with Norrie disease who experience intermittent neurological dysfunction may benefit from β blockade.
We thank the patient for permitting us to report his case and Dr Tony Fryer for helpful discussion.