We present a family with an inherited partial deletion of MAOA
and a complete deletion of MAOB,
resulting in loss of function of both genes. Although there are no previous reports of a genomic microdeletion affecting only MAOA
, the consequences of dual MAO loss of function can be predicted by comparing reports of probands with ND resulting from larger contiguous gene deletions or with selective MAOA loss of function.12, 13, 14, 15, 16, 17, 18, 19
These reports reveal that the presence of either a functional MAOA
gene product is sufficient to preserve intellectual processing and development to within mild to borderline mental retardation levels. However, as described in this report and in atypical ND patients with dual MAO loss, deletion of both genes results in severe to profound mental retardation apparent shortly after birth, indicating that these genes are critical for early brain development and function.
In males, the loss of MAOA
is associated with severe mental retardation and unusual stereotypical behaviours of hand wringing and lip smacking. The stereotypical hand movements and lip smacking were also noted in families with loss of function mutations or deletions of MAOA
Although these stereotypical behaviours are similar to those seen in Rett syndrome and Angelman syndrome, they have distinctive features that can provide a useful diagnostic aid. The absence of clinical manifestations in the female deletion carrier, coupled with the assumption that the random X-chromosome inactivation pattern in lymphocytes is echoed in the central nervous system itself, suggests that mosaic expression of these genes in the brain is sufficient to sustain normal neural development and function.
In a study of an atypical ND patient, Rodriguez-Revenga et al17
suggested that the co-deletion of EFHC2
underlies the seizures observed in their proband, as the paralogous EFHC1
is associated with autosomal juvenile myoclonic epilepsy.23, 24
Although seizures are uncommon in classical ND, there are examples of seizures in cases with NDP
point mutations.25, 26
The occurrence of seizures in the family described here further supports a role for the disruption of several genes in this region being sufficient to cause epilepsy.
MAO inhibitors have been widely used in the past to treat severe depression and, although significant side effects are reported, long-term use is not associated with cognitive decline or with the stereotypical hand movements seen in this family. This suggests that the clinical features we observed are likely to be due to disturbances in the development of serotonin, norepinephrine and dopamine neuronal populations during early embryogenesis and brain formation, rather than being a reflection of altered neuronal function once normal neuronal connections have been established.
There are interesting parallels to the clinical presentations in MAO-deficient mouse models. MAOA
knockout mice exhibit abnormal behaviours, including trembling and increased fearfulness as pups and increased aggression in adult males.27 MAOB
knockout mice display increased reactivity to stress but, as with humans, this phenotype is relatively mild compared with MAOA
The double MAOA
knockout has an extreme behavioural hyper-reactivity compared with single knockouts, again recapitulating the more severe phenotype seen in humans and indicating partial functional redundancy between MAOA
In summary, the likely clinical features of patients with dual MAO deficiency have previously been inferred from patients with selective loss of genes within the region of Xp11.2 and this case confirms the predictions. The distinct clinical phenotype of patients without MAO function should be included in the list of conditions associated with abnormal hand postures and movements.