Rare Genetic Syndromes Associated with Autism: History
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Olga Sysoeva
,
Anastasia K Neklyudova
,
Kirill Smirnov
,
Anna Rebreikina
,
Olga Martynova

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social and communicative skills, behavioral stereotypes, and sensory abnormalities. Its prevalence is one in 54 children, with the number of identified cases rising annually. Atypical sensory processing is one of the key characteristics of autistic people that can have a cascading influence on higher-level functions, such as language or social inference. Behaviorally, sensory abnormalities can present as hypo- and hyperresponsiveness (or hypo- and hyperreactivity). One of potential reasons for this multidirectional deficit is the high heterogeneity of idiopathic ASD (the form of autism where the biological cause of the disease is not identified). 

  • Fragile X syndrome
  • Angelman syndrome
  • Phelan–McDermid syndrome
  • Rett syndrome
  • autism spectrum disorder (ASD)

1. Hypersensitive Syndromes

1.1. Fragile X Syndrome

Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with intellectual disability, social deficits, hypotonia, and anxiety. Its prevalence varies from approximately 1:4000 in males to 1:8000 in females [1], making it the second most common chromosome abnormality that leads to intellectual disability after Down’s syndrome [2]. Intellectual disability is mild or moderate in this syndrome [3]. FXS has a strong comorbidity with ASD, with a prevalence of 22% for both sexes [1][4]. Another frequently associated condition is attention deficit and hyperactivity disorder (ADHD), which occurs in 60–84% of cases [5][6]. FXS patients display weaknesses across all language and literacy domains compared to peers, with particular noticeable impairment being the higher occurrence of word repetition in these patients [7]
Fragile X syndrome is caused by FMR1 gene disruption on the X chromosome that prevents the expression of FMRP, which is involved in synaptic development and plasticity [8]. The disruption of this mechanism affects multiple neurotransmission neuromediator systems, including GABAergic. Studies have found a reduction in the expression of several GABA-A receptor subunits (namely α1,3, 4, β1,2, and γ1,2), suggesting a decrease in phasic inhibition in FXS [9]. Later experiments have reported a decrease in the number of δ subunits, which are located extra-synaptically [10] and are involved in tonic inhibition and the general level of excitability of neural networks [11]. Thus, both phasic and tonic inhibition systems are affected in FXS [12].

Studies of FXS consistently reflect hyperexcitation and hyperresponsiveness of the auditory system in patients and animal studies on both behavioral and electrophysiological levels, suggesting a neurophysiological pathway into the origin of these autistic symptoms. Of note, the neurophysiological hypersensitivity and decreased habituation that led to an increased response to the repetitive stimulation in the case of FXS (probably in both visual and auditory modality) might lead to decreased sensitivity to changes and inattention symptoms, as reflected in attenuated MMN and P3a components. This pattern of results might be linked to the decreased tonic and phasic inhibition found in this syndrome.

1.2. Angelman Syndrome

Angelman syndrome is a genetic neurodevelopmental disorder with a prevalence rate of 1:10,000–20,000 births [13]. The clinical phenotype includes intellectual disability that ranges from moderate to severe and is present almost in 100% of patients, microcephaly, and impairments in motor development, i.e., abnormal gait and coordination difficulties and hypotonia [14][15]. Language development in individuals with AS is severely impaired, from entirely non-verbal behavior to speaking a few words or phrases [16]. Hyperactivity is present in AS, though it decreases with age [17][18]. Autistic-like characteristics are a common symptom and affect 36% of AS patients [1].
Two main genetic causes lead to AS. The first one (nondeletion type) is connected with the UBE3A gene de novo mutations, imprinting defects, and paternal uniparental disomy and account for 25–30% of all cases. Paternal copies of UBE3A are epigenetically silenced in the brain; therefore, the maternal inactivation of UBE3A causes a nearly complete loss of UBE3A selectively in the brain [19]. UBE3A encodes ubiquitin-protein ligase E3A, which is involved in targeting proteins for subsequent degradation by proteasome [20], and is also involved in the regulation of the cell cycle, synaptic plasticity, and cellular protein quality control [21]. The second cause is deletion at the 15q11-q13 locus, which contains UBE3A and in several cases other genes, including those coding different GABA receptors subunits—GABRB3, GABRA5, and GABRG3 [22]. Individuals with deletion AS have a more severe clinical phenotype [15][23].

Even among the patients with similar genetic etiology and relatively homogeneous symptoms that lead to diagnosis of AS, it can be seen that heterogeneity in the sensory processing with both hypo- and hyperresponsiveness reported at the behavioral level. This heterogeneity might be partly caused by the number of genetic abnormalities involved and the implication of additional genes (such as those related to GABA activity) that should be taken into consideration. On the electrophysiological level, it can be seen that hypersensitive patterns, such as frequently occurring seizures, prolonged components of somatosensory ERPs, and generally decreased neuronal noise that can be suggested from elevated slower rhythms (θ and Δ) over the higher ones (β) [24] reported for a subpopulation of AS with the deletion phenotype. Combining these findings with animal models, it can be assumed that the impairment in tonic inhibition leads to the hypersensitive phenotype in patients with AS.

2. Hyposensitive Syndromes

2.1. Phelan–McDermid Syndrome

22q13 deletion syndrome, also known as Phelan–McDermid syndrome (PMS), is a neurodevelopmental disorder characterized by hypotonia, intellectual disability of varying degrees (from severe in a majority of cases to mild in some patients), delayed or absent expressive speech, and dysmorphia [25][26]. Its prevalence according to approximate estimates is between 1:8000–15,000 and the rate of autism in PMS is very high and varies from 50 to 75% [25][27]. It is supposed that 1% of people with autism have Phelan–McDermid Syndrome [28].
PMS is caused by de novo or inherited impairments at the 22q13 locus with the SHANK3 gene as the major candidate gene. The severity of symptoms positively correlates with deletion sizes [29]. The protein product of SHANK3 (it has the same name) is a scaffolding protein in postsynaptic glutamate receptors, including NMDA, mGluRs, and AMPA receptors [30][31]. SHANK3 knockout mice demonstrate a reduction in the expression of parvalbumin (PV), while the amount of GABAergic PV+ interneurons does not change [32]. As decreases in PV leads to increased facilitation of GABA release, the inhibition is increased [33]. A series of animal studies demonstrated that SHANK3 deletion only in the GABAergic interneurons is enough to reproduce the phenotype [34][35], supporting the crucial role of inhibition in the development of PMS.

PMS individuals showed a decreased amplitude of the P50 and P2 auditory components [36][37]. It was reported that weaker γ-band ASSR in patients with PMS as well as with idiopathic ASD [38]. However, data on 40-Hz ASSR in idiopathic ASD is inconsistent as no difference in this response was also reported [39][40], suggesting that atypical γ-band ASSR might be associated with a subgroup of ASD, probably those with abnormalities within a SHANK3-related pathway. This idea has been supported by a high-functioning girl with mild intellectual disability, attenuated language skills, and slightly atypical social and communication functions. She had a drastic reduction of 40-Hz ASSR and SHANK3 microduplication [41], again linking γ-band ASSR with SHANK3 abnormalities. As 40-Hz ASSR reflects the functioning of NMDA receptors on GABAergic interneurons [42][43], its reduction supports the link between the abnormal functioning of local inhibitory connections in PMS patients and potentially in a subgroup of idiopathic ASD.

2.2. Rett Syndrome

Rett syndrome (RS) is a severe neurodevelopmental disorder generally characterized by normal development during the first 6–18 months, followed by a stagnation and a loss of acquired motor and language skills. RS is frequently associated with autistic traits which occur in approximately 60% of cases [1]. Other common symptoms are breath irregularities, abnormal gait, and hand wringing [44][45]. Its prevalence varies from 1:10,000 to 1:20,000 [46]. RS patients are suggested to have severe intellectual disabilities [47], while adequate assessment of cognitive functions are challenging due to severe motor problems and the absence of necessary language skills.
The majority of Rett syndrome cases come from different types of MECP2 gene mutations. Its protein product—MECP2 protein—interacts with a regressor complex of HDACs and SIN3A proteins to repress gene transcription [48][49] and also plays the role of a transcriptional activator [50]. MECP2 affects the activity of more than 60 different molecular pathways, including those involved in spine morphology, dendritic complexity, and mTOR signaling vital for cell growth and metabolism [51]. Of note, MECP2 disruption only in GABAergic neurons seemed to be enough to cause symptoms in mice models [52], pointing to the crucial role of inhibition in the development of RS.

Electrophysiological and phenotypical data concerning sensory deficit in Rett syndrome is inconsistent, suggesting discrepancies between modalities. ERPs studies of auditory and visual modalities suggested hyposensitivity (delayed and decreased amplitudes of P2 and MMN in the auditory modality and reduced N1-P2 and N2 components in the visual modality), whereas somatosensory studies pointed to hypersensitivity. Attenuated and delayed ERPs, as well as steeper 1/f slope of resting EEG with predominance of low-frequency over the high-frequency activity, might be linked to increased tonic inhibition suggested in RS. One possible mechanism of this imbalance in RS is based on increased GABA spillover beyond the synapse [53].

2.3. Tuberous Sclerosis

Tuberous sclerosis complex (TSC) is a genetic disorder with the prevalence of 1:5,500–10,000 live births in the population. It is characterized by benign tumors in multiple organs, epilepsy, attention deficit and hyperactivity disorder, anxiety, sleep disorders, and other behavioral problems [54]. Severe intellectual disability is present in more than half of patients [55]. ASD criteria meet around 25–40% of patients [56][57].
TSC is caused by a mutation in the TSC1 (encodes hamaritine protein) or the TSC2 (encodes tuberine protein) genes. Tuberine and hamaritine act as a complex and inhibit the RHEB protein, which activates mTORC1, a crucial protein for many neurodevelopmental processes, such as the initiation of protein translation and cell growth control [58].

Little is known about hypo- or hypersensitivity tendencies in sensory processing in TSC patients; however, in a case study, sensory dysregulation in daily activities was reported [59].

Electrophysiological evidence suggested hyposensitivity in patients with TSC (delayed visual components and decreased and delayed ERPs in auditory modality). Interestingly, despite downregulated inhibitory currents [60], this syndrome remains mostly hyposensitive. One possible explanation for this was provided from a magnetic resonance spectroscopy (MRS) study, where a decreased number of GABA-A receptors was found in patients with TSC, accompanied by elevated GABA concentration [61]. Authors suggested the elevation of GABA is a compensation mechanism for decreased inhibition. Possibly, the molecular impairments associated with TSC lead to overcompensation and result in a hyposensitive phenotype.

2.4. Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is the most common inherited disorder of the central nervous system with a prevalence that varies from 1:2,000 to 1:5,000 subjects [62]. Phenotypically, NF1 is characterized by multiple cafe-au-lait spots (flat dark patches on the skin), axillary and inguinal freckling, and various and multiple benign tumors in the central nervous system. Patients with neurofibromatosis type 1 are likely to have ASD and its prevalence varies from 10 to 40% [63][64]. Moreover, ADHD is very common in this disorder, being a major contributor to academic underachievement in this population [65]. Intellectual disabilities are not very common in NF1; however, it occurs in a mild degree in 5–30% of patients [66][67].
NF1 is caused by mutations in the NF1 gene located at chromosome 17q11.2; they can be either inherited or de novo [68]. This gene encodes a neurofibromin protein, reduces cell proliferation, and is involved in the development and growth of a variety of tissues [69]. An animal model of NF1 is characterized by an increased activity-dependent release of GABA, suggesting increased phasic inhibition in NF1 [70].

Increased latencies of brainstem auditory evoked potential (bAEP) were found in 15–28% of NF1 patients [71][72]. Findings suggested that abnormalities in auditory processing in the early stages of development can cause the occurrence of ASD symptoms in NF1 [73]. Authors investigated ERPs to repetitive auditory stimuli in infants with NF1 at the age of 5 and 10 months and found decreased age-related changes in the scalp profile of neural responses.

In addition to delayed and decreased early components in different modalities, especially in the visual modality, research focuses on impaired attention in neurofibromatosis type 1. A deficit of attention-related component P3 was reported and the possible cause for that is a reduced sensitivity to sensory stimuli that significantly impact the bottom-up attention switch; however, it failed to be proven experimentally. Interestingly, a later component N450 was shown to be enhanced, which probably corresponds with a compensation mechanism. Taken together, the increased phasic inhibition might be related to attenuated early ERP components, while lower inhibition in the frontal cortex might cause the quicker and smaller attention-related ERPs.

4. Conclusion

To conclude, it is important to say that based on electrophysiological findings it can be subdivided syndromes into two groups with hyper- and hyposensitivity phenotypes. Several indicators that would be useful for assessing sensory impairments in both research and clinical practice were identified. First, it is components of event-related potentials that might point to shifts towards hypo- or hypersensitivity at different stages of information processing. Second, resting state EEG can provide information about tendencies towards inhibition or excitation in the neuronal network, e.g., via such promising parameters as 1/f slope, and evoked and induced γ and α rhythms. The above-mentioned EEG/ERP parameters can be a good candidate for translational biomarkers between animal and patient studies that allow one to capitalize on the more precise understanding of mechanisms and the underlying molecular paths to sensory deficit in syndromic forms of ASD that is possible only in animal studies.

This entry is adapted from the peer-reviewed paper 10.3390/genes13040671

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