Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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Monoamine oxidase-A deficiency is an X-linked disorder affecting the catabolism of serotonin and the catecholamines. Main symptoms are mild intellectual disability and behavioral abnormalities consisting of excessive, sometimes violent aggression. Diagnosis may be inferred from a finding of elevated urinary concentrations of the monoamine oxidase-A substrates, normetanephrine, 3-methoxytyramine, and tyramine, in combination with reduced amounts of the monoamine oxidase products, vanillylmandelic acid, homovanillic acid, 3-methoxy-4-hydroxyphenolglycol, and 5-hydroxyindoleacetic acid. Monoamine oxidase deficiency has been found as an isolated defect affecting monoamine oxidase A and, in combination with a deletion of the Norrie disease gene, as a combined deficiency of monoamine oxidase A and B or an isolated deficiency of monoamine oxidase B. Confirmation of monoamine oxidase-A deficiency is obtained by measurement of the activity of this enzyme in dexamethasone-stimulated fibroblasts. Combined monoamine oxidase-A and B deficiency has similar biochemical consequences. Presentation is with intermittent hypotonia, stereotypic hand movements, and developmental delay.
• Monoamine oxidase deficiency is inherited as an X-linked trait.
• Monoamine oxidase exists in 2 distinct forms encoded by separate genes, monoamine oxidase-A and monoamine oxidase-B, and each has preferential affinities for biogenic amine and other amine substrates.
• Monoamine oxidase deficiency has been described as isolated monoamine oxidase-A deficiency, as a combined monoamine oxidase-A and B deficiency, as a combined monoamine oxidase-A and B deficiency in association with Norrie disease, and as an isolated monoamine oxidase-B deficiency in association with Norrie disease.
• Individuals with monoamine oxidase deficiency should avoid foods or drugs containing amines.
Deficiency of monoamine oxidase has been described in association with Norrie disease (an X-linked syndrome characterized by congenital blindness, hearing loss, and variable mental retardation) (24; 63; 64), as an isolated defect affecting only monoamine oxidase-A, and as a combined deficiency of both monoamine oxidase-A and B in the absence of Norrie disease. Five patients with X chromosome deletions including monoamine oxidase-A and monoamine oxidase-B, as well as the Norrie disease gene, had severe mental retardation, autistic-like behavior, abnormal peripheral autonomic function, and atonic seizures (21; 40), whereas 2 brothers with a complex deletion involving the Norrie disease gene and a part of the monoamine oxidase-B structural gene, but with an intact monoamine oxidase-A gene, had no psychiatric symptoms or mental retardation (03; 40). Norrie disease may occur without affecting either monoamine oxidase-A or -B (45). Involvement of deletions of the X chromosome in areas other than the structural genes for monoamine oxidase-A gene and monoamine oxidase-B impedes interpretation of the clinical data in these individuals.
In 1993, a large Dutch kindred with a new form of X-linked, non-dysmorphic, mild mental retardation was described by Dutch geneticist Han G. Brunner and colleagues at University Hospital Nijmegen in the Netherlands (10). Affected males had a marked disturbance in their urinary monoamine profile that was compatible with a defect in monoamine oxidase. The locus for the disorder was assigned to the region of the monoamine oxidase-A gene. It was later reported by the same group that monoamine oxidase-A activity was deficient in dexamethasone-stimulated cultured skin fibroblasts from affected males and that monoamine oxidase-B activity was normal. The deficient monoamine oxidase-A activity was shown to be caused by a point mutation in exon 8 of the monoamine oxidase-A structural gene, which changes a glutamine (cytosine-adenosine-guanine) codon to a termination (thymidine-adenosine-guanine) codon (09).
In 2001, another family was reported in whom monoamine oxidase deficiency was suspected on the basis of elevated serum serotonin concentrations. The affected mother presented with a history of flushes, headaches, and diarrhea. Her 2 sons had moderate intellectual impairment and attention deficit and hyperactivity disorder (18). Discussion relating to this family, pointed out that similar cases previously had been described (74). In one study, 9 individuals exhibited all of the same features: chronic episodic flushing, diarrhea, headache, psychiatric symptoms, irritability, prostration, increased blood serotonin, and normal or subnormal urinary 5-HIAA concentrations. Monoamine oxidase deficiency was suspected, and a number of metabolic studies were performed that supported the monoamine oxidase deficiency hypothesis (73; 30). Confirmation of the condition by enzyme or mutation analysis was not reported in any of these studies.
In 2010, 2 males were described with a 240kb deletion of Xp11.3-p11.4 that included both monoamine oxidase-A and B genes but excluded the Norrie disease gene (76). A similar case was reported in 2012 (53). All had developmental delay, intermittent hypotonia, and stereotypic hand movements.
No specific defect affecting monoamine oxidase-B without involvement of the Norrie gene has been described.
Mouse models are available for deficiencies of both monoamine oxidase-A (12; 62; 05; Bortolato et al 2011b), monoamine oxidase-B (33), and combined monoamine oxidase-A and B deficiency (15; 07; 65).
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