20 ans après: a second mutation in MAOA identified by targeted high-throughput sequencing in a family with altered behavior and cognition

Abstract

Intellectual disability (ID) is characterized by an extraordinary genetic heterogeneity, with 4250 genes that have been implicated in monogenic forms of ID. Because this complexity precluded systematic testing for mutations and because clinical features are often non-specific, for some of these genes only few cases or families have been unambiguously documented. It is the case of the X-linked gene encoding monoamine oxidase A (MAOA), for which only one nonsense mutation has been identified in Brunner syndrome, characterized in a single family by mild non-dysmorphic ID and impulsive, violent and aggressive behaviors. We have performed targeted high-throughput sequencing of 220 genes, including MAOA, in patients with undiagnosed ID. We identified a c.797_798delinsTT (p.C266F) missense mutation in MAOA in a boy with autism spectrum disorder, attention deficit and autoaggressive behavior. Two maternal uncles carry the mutation and have severe ID, with a history of maltreatment in early childhood. This novel missense mutation decreases MAOA enzymatic activity, leading to abnormal levels of urinary monoamines. The identification of this new point mutation confirms, for the first time since 1993, the monogenic implication of the MAOA gene in ID of various degrees, autism and behavioral disturbances. The variable expressivity of the mutation observed in male patients of this family may involve gene-environment interactions, and the identification of a perturbation in monoamine metabolism should be taken into account when prescribing psychoactive drugs in such patients.

The role of monoamine oxidase A in aggression: Current translational developments and future challenges

“…These studies led to the discovery that Maoa mutants exhibit a broad number of deficits akin to core autistic symptoms, namely social deficits, communication impairments, perseverative behaviors, poor reversal learning and reduced auditory and tactile sensitivity (Bortolato et al, 2013a). Notably, this preclinical evidence was strikingly confirmed by the recent characterization of a new cases of Brunner syndrome in a boy with low-functioning autism-spectrum disorder, exhibiting severe cognitive impairments and episodic self-aggression in response to stress (Piton et al, 2014). Other loss-of-function MAOA mutations were recently identified in males with mild intellectual disability, introverted and obsessive traits, attentional deficits and episodic explosive aggression (Palmer et al, 2015).…”

“…Although this breakthrough was instrumental for the resurgence of biological criminology, progress on the clinical characterization of the phenotypic consequences of MAOA deficiency lagged behind for several years, due to the lack of nosographic details on the psychological and cognitive characteristics of these patients (Hebebrand and Klug, 1995) as well as the rarity of Brunner syndrome. Indeed, several attempts to identify other cases of this disorder proved unsuccessful (Mejia et al, 2001), and a second case of Brunner syndrome was described in the literature only in 2014, approximately twenty years after the first report (Piton et al, 2014). …”

Polymorphisms in the canine monoamine oxidase a (MAOA) gene: identification and variation among five broad dog breed groups

“…No variants were found in exons 1, 7, or 8. SNVs in exon 8 have been associated with Brunner’s disease in humans, a rare recessive X-linked disorder characterized by impulsive aggressiveness and mild mental retardation associated with MAOA deficiency [3, 37]. The exons studied were therefore highly conserved, which is not surprising in view of their importance towards normal MAOA function.…”

A mutation in the enzyme monoamine oxidase explains part of the Astyanax cavefish behavioural syndrome

“…In humans, MAO-A/B sequences seem very constrained as only two point mutations in the coding sequence of MAO-A have been described in patients with intellectual disability and impulsive, violent behaviour 59,60 . The cavefish aminergic condition, including high neurotransmission indexes and a mutation in their MAO enzyme, would probably be considered strongly pathological in humans 61 , yet they thrive in their caves since about one million years.…”