Parallel paths: A narrative review exploring autism and its co-occurring conditions

Abstract

Autism is a heterogeneous condition with a rising prevalence and demand for specialized care. Autistic children are more likely than neurotypical peers to experience co-occurring conditions (CCs), including medical, psychiatric, and behavioral issues, highlighting the urgent need for autism-competent healthcare providers in general healthcare. This review aims to equip primary care providers (PCPs) with a concise summary of common CCs and strategies for effective identification. A panel of experts with extensive experience in caring for autistic children collaboratively summarized key literature, research evidence, and existing clinical trial outcomes, supplementing their clinical expertise. Autistic children consistently show higher rates of both medical and mental health issues. Despite greater healthcare utilization, many autistic individuals report unmet needs. CCs can impair behavior, functioning, and well-being, but are often treatable when recognized early. Timely identification and management of medical and psychiatric CCs are critical for improving outcomes for autistic children and their families. This evidence-based review supports PCPs in enhancing their knowledge, fostering early recognition, and delivering comprehensive, responsive care.

Key Words: Autism spectrum disorder; Comorbidity; Primary healthcare; Neurodevelopmental disorders; Delivery of health care

Core Tip: This narrative review comprehensively explores the wide range of medical, psychiatric, neurological, and behavioral co-occurring conditions (CCs) in individuals with autism. Authored by experts in the field, it synthesizes current evidence and clinical insight to support early recognition and integrated care. Notably, such an extensive and multidisciplinary review of autism CCs has not been previously published, addressing a significant gap in the literature.

INTRODUCTION

Autism is a neurodevelopmental disability (NDD) characterized by core features such as social communication challenges, focused interests, and repetitive behaviors[1]. The prevalence of autism continues to rise, with approximately 1 in 36 children in the United States as of 2020[2]. The presence of medical or psychiatric co-occurring conditions (CCs) has also been associated with greater impairment in adaptive functioning, amplification of autistic challenges, negative impact on the quality of life and economic burden. Consequently, when providing the diagnosis of autism, clinicians should specify whether the diagnosis is accompanied by environmental factors, known medical or genetic conditions, or another neurodevelopmental, mental, or behavioral disorder. Similarly, diagnosing providers should specify whether an intellectual disability (ID) or language impairment is present. These specifiers are frequently used to describe associated symptomatology and the presence of CCs, which can vary over time.

As the prevalence of autism continues to rise, patients frequently present with complex medical needs and higher healthcare utilization than neurotypical peers or individuals with other NDDs, but they also report more unmet medical care needs[3-7]. Many autistic individuals do not have access to specialized care as there are not enough specialists to care for this population. This highlights the pressing need for primary care providers (PCPs) to increase their knowledge about how to support individuals with autism. This includes identifying clinical presentations, as well as improving timely identification and management of CCs, which can frequently and negatively impact the individual and family well-being[8].

Moreover, CCs often accompanying autistic people can affect multiple systems and may vary by age and gender. The precise prevalence of CCs is variable, and may be influenced by the heterogeneity of this population. Research methodological variance-such as study population characteristics, sample sizes, differences in healthcare systems, diagnostic practices, and evolving awareness of autism over time, also affect variability in prevalence. For instance, the prevalence of medical symptoms in autistic individuals ranges widely, from 10.7% (for abnormal growth patterns) to 91% [for gastrointestinal (GI) symptoms][9,10]. In a nationwide Swedish twin study of 19130 subjects from 1992 to 2001, 50.3% of autistic individuals had four or more CCs, while only 4% had no concomitant conditions[11]. Another study involving 42569 autistic individuals found that 74% had at least 1 CC[12]. A retrospective chart review of 1858 autistic children from 2016-2021 reported that 29% had ≥ 1 medical condition[13]. Hossain et al[14] reported two studies estimating the prevalence of at least one co-occurring psychiatric disorder at 54.8% and up to 94%, with attention deficit hyperactivity disorder (ADHD), anxiety, depressive disorders and sleep disorders being the most frequent CCs[14].

It has been postulated that many common comorbidities in autistic individuals may share underlying etiological factors, including pre- and postnatal exposures, also associated with autism[12]. Although not completely understood, CCs in autism can stem from causally independent mechanisms or shared genetic etiology, where genes with pleiotropic effects play a role. In a study of 42564 autistic individuals and 11390 non-autistic siblings (between 1999 and 2019), comparing pre- and postnatal exposures the authors found higher rates of CCs in the autism group. However, the exposure-CCs association in non-autistic siblings suggests that these CCs may occur independently of the autism diagnosis[12]. Shared genetic risk between autism and phenotypes are seen with DDX3X-related neurodevelopmental disorder and gait disturbance, microcephaly and autism in Rett syndrome, SCN1A, SCN2A and KCNJ10 channelopathies that have the same causal genetic mechanism for both autism and epilepsy, SYNGAP1 gene involvement in synaptic plasticity and shared etiological pathways for ID, autism and epilepsy[15-17]. This suggests a shared etiology between these conditions and autism.

CCs in autism may share symptoms and also have atypical manifestations complicating their timely diagnosis[18-21]. For instance, medical symptoms may manifest as new behaviors or worsening of existing ones. Gender differences are also notable, with females having higher neurological and genetic findings[13,22]. Age-related differences in CCs between autistic children and adults are also documented. In a study of 579 autistic individuals and 1897 matched neurotypical peers younger than 2 years of age, the authors found that generalized convulsive epilepsy, nystagmus, delayed milestones, lack of normal physiological development, and strabismus were more likely in those later diagnosed with autism[13]. In another systematic review and meta-analysis, ADHD, sleep-wake problems, somatic symptoms, and related disorders and celiac disease were more common in autistic children/adolescents compared to adults[23]. On the other hand, motor problems, GI symptoms, depression, epilepsy, hearing problems, and neurocutaneous disorders were higher in autistic adults compared to children/adolescents[23]. In a longitudinal cohort of 13382 autistic children enrolled between 2001 and 2009 and followed up till 2011 to observe the time course of development of psychiatric CCs, anxiety disorders occurred first in late childhood. This was followed by depressive disorder, obsessive compulsive disorder, bipolar disorder, and schizophrenia in adolescence[24].

In this narrative review, we aim to explore the diverse range of CCs that occur in autism. Recognizing these CCs is crucial, as frequently atypical presentations can often delay the diagnosis and initiation of appropriate treatment, potentially exacerbating the challenges faced by affected individuals. A comprehensive understanding of common and less-recognized CCs enables clinicians to conduct thorough assessments during appointments, ensuring that no critical aspect of a patient's care is overlooked. Moreover, early identification not only aids in tailoring individualized treatment plans but also facilitates access to specialized services and support for families and children following diagnosis. Such knowledge is essential for guiding interventions, improving overall outcomes, and optimizing the quality of life for autistic individuals and their families. Additionally, by identifying the spectrum of CCs, clinicians and researchers can better advocate for integrated care models and highlight areas where more research and support are needed.

Figure 1 illustrates the distribution of common co-occurring conditions in autism, highlighting ADHD as the most prevalent. Figure 2 depicts the distribution of co-occurring medical conditions, with neurological conditions being the most frequent in autism.

Figure 1 This visualization illustrates the distribution of co-occurring conditions in autism. Attention deficit hyperactivity disorder is the most common co-occurring condition, affecting 35.3% of individuals, followed by learning disability at 23.5%, and intellectual disability at 21.7%. ADHD: Attention deficit hyperactivity disorder; OCD: Obsessive compulsive disorder; ASD: Autism spectrum disorder.

Figure 2 A retrospective analysis of medical records for 1858 children was conducted. Neurological conditions were the most common, affecting 37% of children (seizures most common in 7.79%). Other conditions include refractory errors (7.05%), strabismus (5.94%), and plagiocephaly and/or torticollis (5.94%). ENT: Ear, nose, throat.

AUTISM PRESENTATION ASSOCIATED WITH KNOWN ENVIRONMENTAL EXPOSURES

Autism can be associated with known environmental factors that can include exposures such as valproate, intrauterine alcohol exposure, prematurity, etc. Different pregnancy-related factors are associated with autism, including perinatal factors such as maternal cervicovaginal infection, low Apgar scores, fetal distress, birth trauma, low birth weight, small for gestational age, and even indirect hyperbilirubinemia[25]. Postnatal factors such as hypoglycemia, intracranial hemorrhage, cystic leukomalacia, and bronchopulmonary dysplasia have been implicated[25,26].

Preterm birth accounts for 1 in 9 births in the United States[27]. Prematurity is a significant risk factor for multiple NDDs (including autism) that persist into adulthood[28]. Up to 20% of ex-preterm infants test positive on autism screening tests and 6% on diagnostic assessments compared to the global rate of 100 per 10000 in the general population[29,30].

This increased risk has an inverse relationship with gestational age, with studies showing nearly a 10-fold increase in autism risk for infants born between 23- and 28 weeks gestation[25].

The neurobiological basis for prematurity and autism appears to be due to the interruption of critical developmental processes. Preterm infants miss a crucial period of accelerated cerebellar growth, typically around 28 weeks of fetal life[31]. They also face an increased risk of cerebellar hemorrhage after birth[32]. Neuroimaging studies at term-equivalent age have revealed reduced volumes in regions crucial for social behavior, including limbic, insular, occipital, and temporal areas, with these structural alterations persisting into adolescence[25].

Some have described the pathogenesis as the "triple threat hypothesis", where the vulnerable preterm brain encounters exogenous stressors during critical developmental periods. Multiple risk factors contribute to this vulnerability, including maternal infections and subsequent fetal inflammatory responses[25]. The Extremely Low Gestational Age Newborn Study demonstrated that elevated inflammatory neurotrophic proteins in newborn blood during the first month of life correlate with increased risk for autism[33]. This is consistent with observations of inflammatory markers in the brain and cerebrospinal fluid of ex-preterm neonates with autism[25]. Additionally, maternal obesity, a pro-inflammatory state, is associated with up to a tenfold increased risk of positive autism screening at age 2, with this risk further elevated when accompanied by maternal diabetes[25].

Screening for autism in preterm populations presents unique challenges. The Modified Checklist for Autism in Toddlers (M-CHAT), while widely used, shows limitations in the ex-preterm population. A study showed it to have a positive predictive value of only 20%, with 21% screening positive on the M-CHAT at 2 years of age and only 7% being diagnosed at age 10[34]. This discrepancy reflects the tool's sensitivity to other neurodevelopmental delays common in preterm infants, such as those related to vision, hearing, and movement[34].

The Autism Detection in Early Childhood tool has emerged as a more suitable alternative, demonstrating superior sensitivity (0.89) and specificity (0.98) in distinguishing autism from other NDDs in preterm infants[35]. Compared to a sensitivity of 0.52 and specificity of 0.84 of the M-CHAT. It is brief and easy to use and does not require additional training[35].

Autism in preterm infants often presents with a distinct phenotype characterized by prominent social interaction and communication impairments but less pronounced repetitive behaviors[25]. This early social impairment may contribute to documented differences in social relationships observed in adulthood in ex-preterm infants compared to peers. Relationships with parents often remain stronger than those with their peers. Difficulties in initiating relationships were responsible for the relationship challenges[36].

Early intervention is crucial, with systematic reviews emphasizing the importance of individualized, parent-involved interventions that target a broad range of learning objectives[37]. An early intervention pilot in Spain that focused on ex-preterm toddlers with autism showed promise in improving social communication and cognitive outcomes. The toddlers received social-communication interventions, and most participants in the intervention group showed significant improvements in social- communication skills, cognitive development, and language abilities[38].

Understanding this complex interplay between biological vulnerability and environmental stressors in infants remains crucial for improving outcomes. Future directions should focus on developing preterm-specific screening methods. Life course intervention strategies that address this population's unique neurodevelopmental and life-course trajectories are essential[39].

Neurological conditions

Autism is commonly associated with various neurological CCs that significantly impact the overall presentation, management, and outcome of the condition. Amongst the CCs associated with autism, neurological disorders are reported to be the most prevalent[13]. These neurological issues include mainly motor impairments, cerebral palsy (CP), epilepsy, and sleep disorders. They have an impact on the behavior and cognitive function of autistic children, and the neurological conditions are associated with worse developmental outcomes and increased healthcare needs[40]. Moreover, the clinical approach is more complex, particularly because of drug interactions and the cognitive and behavioral side effects of medications[41]. Clinicians should be aware of the recognition and treatment of these conditions, as it may improve the function and outcome of autistic children[42,43].

These neurological CCs vary in their severity and impact on individuals throughout their lives, and their understanding and proper interventions can help provide more comprehensive care and support for autistic individuals. Pan et al[44] conducted a systematic review and meta-analysis to understand the association of neurological CCs and autism. Although there are several studies focused on investigating the frequency and specificity of neurological disorders in autism, it remains largely unknown, and there is a lack of longitudinal studies investigating the prevalence and the association of neurological CCs and autism[44]. Some of the most common neurological CCs seen in autism are described below.

Epilepsy: Epilepsy is more common in autistic individuals compared to the general population. In a recent review, higher rates of epilepsy in autism compared to their neurotypical peers were reported [odds ratio (OR): 3.26-24.2][44]. Seizure type may include generalized tonic-clonic seizures, absence seizures, and focal seizures. Absence seizures could be easily missed in this population due to their lack of overt motor signs and brief symptom duration (usually between 5 and 20 seconds), and could be mistaken for “daydreaming” episodes of behavioral origin. Clinicians should be aware of developmental regression in autism, as it could presage the onset of epileptic activity even in cases where seizures are subclinical, observable only through electroencephalogram monitoring. Developmental regression could be identified as loss of previously acquired language, worsening in social skills, loss of motor skills (difficulties with previously acquired fine and gross motor abilities) and increased irritability and emotional dysregulation. Developmental regression could mark the onset of an epileptic encephalopathy. Sleep disorders, which are highly prevalent in autistic children, may be further exacerbated by the presence of epileptic seizures.

While the bidirectional and temporal relationship between childhood epilepsy and autism remains unclear, autism is commonly observed in infants with epileptic encephalopathy (such as infantile spasms); epilepsy could lead to autism and, reversely, abnormal brain circuitry underlying autism could predispose the brain to seizures. Early intervention targeting social and cognitive challenges in this population may positively influence developmental outcomes. However, diagnosing autism early in patients with epilepsy is challenging due to the variability in clinical phenotypes[17].

Although there is no specific epilepsy syndrome associated with autism, common biological and molecular pathways between both have been suggested. Common neurobiological factors may contribute to atypical brain development, leading to both conditions. Some of the mechanisms that are thought to be present in both conditions are: Abnormalities in synaptic growth, imbalance in neuronal excitation-inhibition and abnormal synaptic plasticity. With our increasing knowledge of genetic etiologies, it has been described that several genes are implicated in both autism and epilepsy, mainly related to abnormalities in ion channels (SCN1A, SCN2A, GRIN2D, CACNA1), synaptic function and structure (PCDH19, CDKL5), transcription regulators (SYNGAP1, MECP2) with special focus on mTOR pathway in mTOR-pathies (TSC1, TSC2, GATOR). One of the genetic pathways that is most classically described is between infantile spasms and autism in the context of tuberous sclerosis complex[17]. Knowledge about the common underpinning mechanisms is crucial in discovering future drug therapies and in delivering precision medicine.

Hirosawa et al[45] reported higher rates of interictal epileptiform discharges (IED) in autistic children compared to their neurotypical peers. These findings may not suggest that IED is pathogenic in these children, but might reflect epiphenomenal or compensatory processes[46].

Little is known about the impact of epilepsy on social and cognitive function in autistic children, making our understanding of how epilepsy influences social communication or repetitive behaviors challenging. Here, we may differentiate between patients with early severe epilepsy who develop autism, and on the other hand, autistic children that are developing epilepsy. Autistic children with co-occurring epilepsy often demonstrate more severe core autism symptoms and disruptive behaviors than those without epilepsy[17]. There are different known risk factors that increase the likelihood of epilepsy in this population, such as ID, syndromic autism and female gender.

To date, the treatment of autistic patients with epilepsy has been symptomatic (anti-seizure medication, social functioning training and behavioral and cognitive treatment). Antiepileptic medication in these children has positive effects, while controlling seizures and potentially improving overall functioning. However, careful management is essential to minimize side effects and ensure that both autism-related symptoms and epilepsy are effectively addressed. Close monitoring by healthcare providers is important to find the right balance in treatment effectiveness and side effects.

The clinical evaluation of children with early-onset epilepsy should incorporate the assessment of autistic traits. Understanding the biological pathways shared by both may help identify treatment targets to improve epilepsy, comorbid autism, and global neurodevelopment[17].

Motor disturbances: Motor delays and motor disorders are prevalent, with around 80% of children at risk for motor impairment, and they are consistently observed from the first year of life and can persist into adulthood[47,48]. Deficits have been observed in areas such as strength, posture, gait, coordination, and skilled movement performance (praxis). Clinicians should be aware of impairments in fine and gross motor skills, lower balance, difficulties in gait control and weakness or hypotonia, as could be early signs that interferes with global development and daily functioning. Understanding motor impairments is clinically important, because motor function plays a crucial role in various aspects of development, including language, social interaction, and learning. The risk of motor impairment has been associated with increased risk of social communication, repetitive behavior, cognitive and functional impairment. The lack of a complete movement repertoire may affect the play and interaction with peers and caregivers and increase social-emotional difficulties[47]. Additionally, by examining the timing and specificity of motor impairments, we may be able to identify motor markers that could help with earlier diagnosis of the condition. Early gross and fine motor development within the first year of life predicts the rate of language development in autistic children and is related to the future outcome in this population. It has been demonstrated that motor impairments may be associated with a more severe phenotype, predict the level of adaptive functioning and some studies have also found that they are related with lower IQ scores[47].

One of the main challenges is developing assessment tools and standardized scales that are suitable for different developmental stages, particularly for infants and young children, to accurately assess and characterize motor impairments. For clinicians, early detection of motor delays in children is as important as early detection of autism or global developmental delay.

We describe below the range of motor disturbances that may be present in patients with autism spectrum disorder (ASD).

Repetitive behaviors: Stereotypies: The presence of repetitive behaviors or stereotypies is the only motor disorder that is included in the Diagnostic and Statistical Manual of Mental Disorders diagnostic criteria for ASD. Classically it was explained as “self-stimulatory”, but lately it has been considered as an involuntary movement disorder.

The prevalence of stereotypies is higher in low functioning patients and with more impaired social and communication domains. The behaviors described as the most specific are hand/finger and gait stereotypies. Goldman et al[49] suggest stereotypies are explained by deficit in the cerebellar and fronto-striatal network that may be specific to autism, especially if cognitive impairment is present.

These findings suggest that clinical severity may be predicted by the presence of stereotypies. Moreover, it has been described that social skills intervention can enhance repetitive behaviors[50]. Stereotypic movement disorder should be considered as an additional diagnosis when stereotypies cause self-injury and become a focus of treatment[51].

Motor delay and dyspraxia: It has been reported that there are impairments in praxis in autistic patients, with poor motor execution[52]. Many autistic individuals experience issues with motor coordination, such as difficulties with fine and gross motor skills. They have also found that dyspraxia, known as the difficulty in performance of skilled movements, is significantly correlated with social, communication and behavioral deficits. Conditions like developmental coordination disorder may co-occur, leading to challenges with activities such as writing, walking, or sports[53].

Gait problems: Gait difficulties have been studied in autistic children such as toe-walking, ataxia, incoordination, postural abnormalities in the head and trunk. Some authors have found significantly more motor incoordination and postural instability in this group[44]. Gait problems may impact their motor development, daily functioning and overall quality of life. Early identification and intervention may improve mobility and the whole global outcome.

The recommendations for clinicians to better assess motor impairments in autistic patients are[54]: (1) Perform a comprehensive clinical assessment: Medical history with motor milestones, neurological exam, with special emphasis in musculoskeletal exam and gait analysis; (2) Early intervention and therapy: Physical therapy, occupational therapy; (3) Follow up: Assess progress and educate families in detection of worsening motor difficulties; and (4) Multidisciplinary approach, in collaboration with physiotherapists, occupational therapists, neurologists, orthopedists.

Movement disorders, Tics, Tourette Syndrome: Tic disorders, such as Tourette Syndrome (TS), are more common in autistic individuals than in the general population[55]. Tics are sudden, involuntary, and repetitive movements or sounds that can be motor or vocal in nature. The presence of tics can sometimes complicate the diagnosis of autism and may require different management and therapeutic approaches.

Tics can be suppressed voluntarily to some extent but often with a sense of anxiety that is relieved only by “release” of the tic. Situations that generate anxiety may exacerbate the tic. They can vary in complexity and range from simple motor tics through complex tics. Phonic tics can also be simple or more complex to elaborate verbal outburst. To better differentiate tics from other movement disorders, a medical history and examination may be necessary to identify those telltale signs: Tics are better typified by the child being able to reproduce them, voluntarily having partial control over them and not interfering with voluntary activity[56].

Individuals with TS, which is characterized by involuntary motor tics and vocalizations, may also be diagnosed with autism[57]. Research suggests that there is an increased likelihood of individuals with TS also having co-occurring autism, especially in those with more severe or complex presentations. It has been discussed that there may be a common genetic etiology between both conditions. The genes NRXN1, CNTNAP2 and SLITRK5 involved in synaptic function and neuronal connectivity have been implicated in both conditions[58]. The management of tics in autistic patients requires an individualized approach. First-line treatment primarily consists of behavioral interventions, such as Comprehensive Behavioral Intervention for Tics and Applied Behavior Analysis, while pharmacological therapy is considered a secondary option. Although not first-line, pharmacological approaches recommended are: Dopamine antagonists (aripiprazole or risperidone) but they may exacerbate social withdrawal in autism; α2-adrenergic agonists (clonidine or guanfacine) effective for tics and ADHD-like symptoms; selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, sertraline) to manage co-occurring anxiety and obsessive-compulsive symptoms[59]. Indications for pharmacological treatment include severe complex tics, significant emotional or psychological distress, comorbid depression, or physical complications such as pain or muscle contractures resulting from the tics.

Neurological syndromes: There are several syndromes that are associated with autism or have autism-like features. With macrocephaly: PTEN, Fragile X syndrome (FXS), Sotos syndrome; With microcephaly: Rett syndrome, MECP2-related disorder. No significant differences were found in the meta-analysis in the risk of microcephaly or macrocephaly between autistic individuals and neurotypical controls[44].

Other syndromes: Angelman syndrome, Williams syndrome, Cornelia de Lange syndrome, Prader Willi syndrome.

Chiari malformation: Some autistic individuals may also have Chiari malformation. This condition is associated with neurological symptoms like headaches, dizziness, and balance problems.

Neurocutaneous disorders: Neurofibromatosis 1, tuberous sclerosis complex. A clinical evaluation and genetic screening aimed at ruling out possible syndromes associated with autism are crucial.

Cerebral palsy: Children with CP, especially those with more severe forms of CP or significant cognitive impairments, have a higher risk of also being diagnosed with autism[60]. Studies suggest that about 4%-16.7% of children with CP may also have autism, although this percentage can vary depending on the population and severity of the conditions[61]. A multidisciplinary approach is needed to achieve a comprehensive and successful management of these patients, including but not limited to neurologists, physiotherapists, psychologists and occupational therapists[56].

Migraine/headache: It has been reported that the odds of migraine/headache in autism are 1.85 times higher than for those without autism [pooled OR 95%CI: Children 1.85 (1.43–2.40)][44]. Some studies reported that autistic children had lower prevalence of headache/migraine than those with ID[44]. The management of headaches in the autistic population is the same as general population, with special emphasis in preventive measures and psychotherapy.

Other neurological disorders: Other CCs such as congenital nerve system abnormality, demyelinating diseases, hydrocephalus or brain injury have been studied in relation to autism, with inconsistent and heterogeneous results published.

It is important to add that some neurological complications in autism may be cared for by general pediatricians or neurologists, even prior to diagnosis of autism. The presence of these CCs can significantly impact the individual’s daily functioning and quality of life. As a result, a comprehensive approach to treatment, involving a multidisciplinary team, is often necessary to address both the core symptoms of autism and any neurological CCs. More concrete guidelines might help to clarify the clinical management for autistic individuals with neurological disorders[44]. Future research objectives may focus on the etiology, molecular and genetic mechanisms, and therapeutic approaches for better managing neurological disorders in these children. Special attention should be given to epilepsy, movement disorders and sleep disturbances, as these are the most common conditions affecting their quality of life.

Abnormal brain imaging: Some studies have shown that autistic children often exhibit increased total brain volume, atypical cortical development, and early overgrowth of the amygdala, which may be associated with the social and emotional difficulties characteristic of the disorder[62-65]. It has been reported that there is a relation between increased Gray Matter Volume (GMV) and autism. Cai et al[66] investigated structural differences between autistic individuals with normal or high IQ (> 70) and low IQ (< 70). They found that both groups showed abnormalities in the same brain regions; however, autistic individuals with low IQ exhibited more widespread neuroanatomical differences. For example, increased GMV in the left inferior temporal gyrus was observed in both groups, whereas increased GMV in the left medial temporal gyrus was unique to the low IQ group. Additionally, children with low IQ showed increased GMV in the right medial superior frontal gyrus and exhibited altered connectivity in frontal and temporal regions involved in social cognition[66]. Other studies have shown a relation between autism and altered functional networks in social cognition-related brain regions, leading to a potential neuroimaging biomarker for autism[67]. Brain imaging is not routinely done in the clinical evaluation of autism. Clinicians should indicate brain imaging when autism co-exists with developmental regression, focal neurological signs, epileptic seizures, macrocephaly or microcephaly in order to rule out structural brain abnormalities such as cortical developmental malformations.

Sleep disturbances

Sleep is fundamental in typical development and plays a vital role in the physical and cognitive maturation of children. Autistic children often do not experience typical sleep. Instead, autistic youth frequently experience significant sleep disturbances, which can exacerbate core symptoms (e.g., challenges in communication, social interaction, and repetitive behaviors). Infant and childhood sleep and circadian development are the foundations of healthy sleep habits throughout life. Understanding the intricate relationship between autism and sleep disturbances is essential for developing effective therapeutic approaches to improve the quality of life for children and their families. Here, we explore the prevalence, types, underlying mechanisms, consequences, and management of sleep disorders in autistic children.

Parent-reported survey evaluations reveal that sleep disturbances are prevalent in 50%-80% of autistic children, significantly higher than in typically developing children (20%-30%)[68-70]. Common issues include difficulty initiating and maintaining sleep, frequent and prolonged nighttime awakenings, early morning waking, irregular sleep-wake schedules, and reduced total sleep duration[71-73]. Additionally, autistic children may exhibit excessive daytime sleepiness and behaviors such as nighttime laughing and talking[74].

Polysomnographic studies have demonstrated distinct sleep patterns in autistic children, including increased nighttime awakenings, reduced total sleep time, lower sleep efficiency, reduced rapid eye movement (REM) and non-REM sleep, and longer sleep onset latency[74,75].

These disruptions are often chronic and persistent throughout infancy, childhood and all through adulthood. In addition to these general sleep disturbances, autistic children experience a higher level of sleep disorders including insomnia which encompasses behavioral bedtime settling challenges and bedtime anxiety, circadian rhythm disorders resulting from abnormal melatonin levels, obstructive sleep apnea resulting from hypotonia and enlarged tonsils, parasomnias such as sleep walking, night terrors, sleep paralysis, and confusional arousals, as well as restless legs syndrome which can significantly fragment sleep[76-80].

The causes of sleep disturbances in autistic children are multifaceted, involving a complex interplay of genetic, neurological, behavioral, and environmental factors.

Neurological factors: Dysregulation of the hypothalamic-pituitary-adrenal axis and altered neurotransmitter pathways contribute to sleep problems in autism[81]. Specifically, reduced melatonin production and increased serotonin secretion disrupt circadian rhythms[82]. Deficits in GABA neurotransmission present in many disorders can interfere with sound sleep.

Genetic influences: Mutations in genes involved in sleep regulation, such as CNTNAP2, FMR1, MECP2, NLGNs, NRXNs, and SHANKs, have been implicated. Variations in the ASMT gene, which impacts the serotonin-melatonin synthesis pathway, further contribute to sleep abnormalities[83,84].

Behavioral and sensory challenges: Behavioral rigidity, sensory sensitivities, and difficulties establishing bedtime routines exacerbate sleep issues. Environmental factors, such as light exposure and noise sensitivity, also play a role[85].

Consequences of sleep disturbances

Impact on the child: Sleep disturbances are associated with increased behavioral challenges including aggression, self-injury, anxiety, hyperactivity, irritability, inattention, increased sensory sensitivity, exacerbations of repetitive behaviors, more pronounced impairments in social communication[74]. They also exacerbate core symptoms, such as repetitive behaviors and social communication deficits, and contribute to cognitive impairments, including reduced attention and memory deficits[86].

Impact on families: Poor sleep in autistic children significantly disrupt family dynamics. Family members of autistic youth are significantly affected by the child’s poor sleep quality and quantity. Higher rates of sleep disruptions in autistic children are closely linked to higher rates of caregiver burden and family stress–indicating sleep disruption in family members[74]. Sleep problems contribute to caregiver stress, depression, and reduced overall family functioning. Parents often report disrupted sleep and emotional exhaustion.

Sleep disturbances and sleep disorders in these children are more resistant to intervention, complicating management efforts. Managing sleep disturbances requires a multidisciplinary approach and early intervention is key.

Behavioral interventions: Behavioral strategies, such as sleep hygiene education, bedtime routines, and positive reinforcement, have shown efficacy in improving sleep in autistic children[87]. Creating a calming sleep environment, reducing sensory stimuli, and maintaining consistent lighting are particularly helpful in children with sensory sensitivities that disrupt sleep.

Pharmacological interventions: Melatonin is commonly prescribed to regulate sleep-wake cycles. Studies have shown that melatonin supplementation can reduce sleep latency and increase total sleep duration in about 53.7% of autistic children[88,89]. Improved sleep in children often leads to better sleep for caregivers as well. Other medications, such as clonidine and gabapentin, are sometimes used but require careful monitoring for side effects.

Treatment of CCs: Addressing underlying conditions such as anxiety, obstructive sleep apnea, restless leg syndrome can significantly improve sleep quality in autistic children.

Further research is needed to better understand the mechanisms underlying sleep disturbances in autistic children and to develop tailored interventions. The integration of wearable sleep-monitoring devices and advancements in telehealth can facilitate long-term management and individualized care.

Sleep disturbances are a significant and pervasive issue in this population, profoundly impacting their development and family dynamics. A multidisciplinary approach that combines behavioral, pharmacological, and environmental interventions is essential for effective management. Addressing sleep issues not only improves their quality of life but also enhances their potential for social and cognitive development.

GI CCs

GI problems are frequently reported among autistic children. These conditions contribute significantly to the disease burden associated with autism, though estimates of their prevalence vary substantially due to differences in sampling and measurement, as well as the heterogenous presentation of autism[90,91]. Many causal and therapeutic hypotheses of autism involve the GI system, including the concept that there is a specific GI pathology associated with autism, triggered by altered immune function or increased intestinal permeability[10]. Though some studies suggest that autistic children may be at higher risk for gluten sensitivity, lactase deficiencies, and even intestinal inflammation, a unique GI pathophysiology specific to this population is yet to be identified[92]. Current clinical practice guidelines, designed for evaluation and management of autism by primary care physicians, do not include routine consideration of potential GI or digestive problems[93,94]. Common problems, like gastroesophageal reflux or constipation, can present atypically, manifesting as stereotypical behaviors or aggression. Consequently, GI problems that may be easily recognized in a neurotypical child may go undiagnosed in autistic children. Many autistic children may be nonverbal or minimally verbal, making it difficult for them to clearly communicate information about pain or discomfort. Indeed, even autistic individuals who have acquired verbal communication skills may struggle with describing subjective experiences or symptoms. It is posited that autistic patients perceive and process pain differently from their neurotypical counterparts, due to alterations in pain perception, transmission, modulation, and expression. The interaction between molecular and neurophysiological pathways of pain processing in this population can result in unique cognitive and behavioral strategies for coping with discomfort[95]. Consequently, the challenge of identifying and studying GI dysfunction in autism warrants adoption of a lower referral threshold to a gastroenterologist if a GI disturbance is suspected[92].

The most common GI concerns among autistic individuals include constipation, diarrhea, and abdominal pain, all of which have been found to be more common among autistic children compared to neurotypical peers[10,96]. Recent studies suggest that autistic individuals and GI symptoms are more likely to experience anxiety and mood problems, and exhibit aggressive, self-injurious behaviors[97,98]. These symptoms can be associated with discrete behavioral issues, like encopresis, delayed toilet training, and atypical eating patterns, further compounding the burden of this condition on patients and families. We caution that associations between GI symptoms and autism should be considered in the context of several limitations. There is insufficient data to determine whether GI symptoms intrinsically linked to an organic pathology, like food allergies (FA), gastroenteritis, or inflammatory bowel disease, occur more frequently in autistic children than in neurotypical children. Furthermore, questions remain about the relative contribution of behavioral factors, such as toileting and feeding problems, to the observed association between diarrhea, constipation, and abdominal pain. Estimates suggest that > 95% of all childhood constipation is functional in origin. Many autistic children experience absent or delayed initiation of toilet training, as well as higher rates of problem behaviors related to toileting routines, thus precipitating development of chronic constipation[99]. Difficulty with sensory processing and motor coordination may lead to fecal retention, impacting GI motility and defecation physiology. Increased rates of constipation are also likely affected by food selectivity in this population, as dietary patterns in autism are frequently characterized by minimal intake of fiber-containing foods that would provide a natural laxative effect and decrease intestinal transit time[100].

Feeding challenges increase the risk for medical sequelae, intensifying concerns for possible GI dysfunction in pediatric autism patients. Autistic children have a fivefold increased risk of developing feeding problems when compared to typically developing peers[96]. The etiology of these atypical and restrictive eating patterns remains elusive, though is surmised to involve pathophysiology of the GI tract. Organic conditions like gastroesophageal reflux, dental anomalies, FA, or infectious/inflammatory gastroenteritis can trigger painful or uncomfortable eating, playing an important role in the development of chronic feeding problems in the general pediatric population. A definitive link to account for the emergence and persistence of feeding problems associated with autism, however, has yet to be identified. Severe food selectivity is the most common feeding problem documented in autistic pediatric patients, with many voicing preference for starches and highly processed snack foods over fruits, vegetables, and proteins[100]. It is not uncommon for feeding challenges to be overlooked relative to other areas of clinical concern, as these selective eating patterns are not always associated with the growth failure or compromise that typically triggers clinical attention in the pediatric setting. Atypical dietary intake patterns in autism do place this population at risk for long-term medical or nutritional complications that may not be adequately captured by anthropometrics alone, including vitamin and mineral deficiencies and compromised bone growth[101]. The interconnection between dietary choices, patients’ sensory experiences of pain or discomfort, and perceptions by parents and caregivers serves to highlight the role for broad, longitudinal, objective studies of feeding patterns, behavior, and GI symptoms.

We note a significant need for increased methodological rigor when defining and assessing GI symptoms in autistic patients. Most published studies utilizing chart review or other established databases have unique operational definitions of GI symptoms, impacting estimates of prevalence. For example, some studies assessing diarrhea in autistic patients focus on stool frequency and consistency, while others provide specific definitions of GI symptoms that would lead to this diagnosis[102-104]. Future inquiry into the relationship between GI symptoms and autism should consider the influence of early feeding practices and environmental factors on the gut. Prior studies of fecal DNA suggest that certain bacterial clusters are overrepresented in autistic children and GI complaints when compared to neurotypical peers with similar clinical concerns[105]. Autistic children are thought to struggle more with breastfeeding, which promotes development of the microbiome and attendant GI mucosal defenses[106]. It is therefore theorized that this suboptimal breastfeeding may result in atypical colonization of the gut microbiome in autism. Alterations in the composition of the gut microbiome may potentially explain anecdotal reports of improvement in behavior following dietary modification, particularly if these changes serve a probiotic function by mitigating common GI symptoms like bloating, pain, and flatulence[107]. Dietary interventions like elimination diets (e.g., gluten- and casein-free diets), nutritional supplements, enzymes, and antimicrobial cocktails continue to be explored as autism-focused treatments, though their use has not been substantiated by empirical investigation[107,108]. Given the popularity of many of these dietary recommendations among the autism community at large, further investigation is warranted to better validate their use.

It would be remiss of us to ignore the firestorm of controversy surrounding the alleged role of routine childhood vaccinations in autism and GI tract dysfunction, infamously suggested in a now retracted study. It is not unreasonable to presume that this cause célèbre deterred clinicians and investigators from investing resources into examining GI health in autistic patients, limiting our ability to create a standardized approach for assessment. Review of the scientific literature does indicate that a greater risk for GI concerns (e.g., abdominal pain, diarrhea, constipation) exists in these patients, though the etiology of these observations remains unclear. Moreover, data on prevalence of symptoms associated with primary digestive disorders (e.g., allergic GI disease, inflammatory bowel disease, celiac disease) in autistic patients is insufficient[96]. Consequently, it stands to reason that the rate of GI pathophysiology in autism is similar to that seen in neurotypical children, with no evidence to support the presence of a GI pathology unique to autism alone[10]. It remains difficult for physicians to assess disease severity and navigate the diagnostic and early intervention process in the absence of standardized tools designed for evaluation of GI symptoms in autistic children. Furthermore, physicians would benefit from guidance on how to modify clinical practice with consideration to the unique combination of behavioral, neurological, or medical issues associated with autism. The current standard of care for these children requires addressing their GI symptoms in a manner identical to that of their neurotypical peers, while simultaneously acknowledging the distinctive behaviors that may be the only sign of true GI pathology. Specialized GI evaluation should be specifically considered for autistic patients who struggle with feeding difficulties and may be at risk for attendant nutritional deficiencies. This enables accurate identification of pathology, as well as prompt referral to occupational or feeding therapy. Future research directions should focus on clarifying the etiology, prevalence, and severity of GI symptoms in the autism population, with special investigation into the contribution of factors such as the gut microbiome, motility, immune dysregulation, and toileting/feeding behaviors.

Allergic disorders

Allergic disorders are caused by dysregulated responses of the immune system to allergens in the environment. Allergic diseases can affect many organs including the respiratory tract, skin, digestive system leading to allergic rhinitis (AR), allergic asthma, atopic dermatitis (AD), FA among others. Atopic diseases are among the most common chronic conditions. The recent National Health Interview Survey (NHIS) reveals that 31.8% of adults and 27.2% of children have one or more allergic conditions including seasonal allergies, eczema, FA. In 2021, about 1 in 5 children had a seasonal allergy (18.9%), 1 in 10 had eczema (10.8%), and 1 in 20 had a food allergy (5.8%) (CDC)[109,110]. The relationship between allergic disorders and autism has been of great interest to the public and scientific community. Although there is conflicting evidence regarding the causal relationship between these two disorders, many studies have shown that allergic disorders are associated with increased risk of autism[111]. A cross-sectional study using NHIS data from 1997 to 2016 shows that children with food, respiratory, and skin allergies are more likely to have autism[112]. This analysis included 199520 children and amongst them, food allergy, asthma and AD were higher in autistic children (11.25%, 18.73%, and 16.81%, respectively) compared with children without autism (4.25%, 12.08%, and 9.84%, respectively). Similarly, a case-control study by Jyonouchi et al[113] found that when all atopic disorders were considered, the risk for autism was strong with a hazard ratio of 3.4 or an odds ratio of 1.24. In a recent systemic review by Billeci et al[114], the authors also found that overall, evidence suggests that individuals with atopic disorders are at increased risk of developing ASD. Individually, each atopic disorder is also observed at higher prevalence in the autistic population. Data from the 2007 National Survey of Children’s Health showed that the prevalence of autism was significantly increased in children with AD (2.19 vs 0.89% in the group without AD; P < 0.0001)[115]. In a national health database from Taiwan by Chen et al[116], higher prevalence of asthma was found in autistic children compared to neurotypical controls (23.3% vs 15.3%)[116]. Meta-epidemiological study by Wei et al[117] revealed that AR patients have increased risk of developing ADHD (OR: 1.90; 95%CI: 1.26–2.8) and ASD (OR: 1.34; 95%CI: 0.86–1.0)[117].

Early childhood development of atopic conditions was found to contribute to the risk of developing autism or ADHD later in life. Cohort with atopic diseases occurring before age 3 was found to have higher prevalence of autism (0.8% vs 0.2%; P < 0.0001)[116]. Wei et al[117], similarly, also showed that presence of allergic disorders in early childhood (mean age of allergic diagnosis 4.5 ± 4.3 years) significantly increased the risk of developing ADHD, autism or both.

Immune dysregulation and inflammation are both typical features in allergic disorders and neurodevelopmental disorders indicating a link in their pathophysiology. Allergic disorders are characterized by immune responses involving activation of Th2. Activated Th2 lymphocytes produce interleukin (IL)-4, IL-13, and IL-5, which are responsible for IgE production by B cells, eosinophil activation and recruitment, activation of mast cells and basophil cells[118]. The balance between Th2 and Th1 immune response regulates the inflammation and tissues remodeling. Skewing of Th2 response leads to the development of allergic disorders. Similarly, some evidence has shown that upregulated proinflammatory cytokines play an important role in pathophysiology of ASD. Croonenberghs et al[119] found increased IL-6 and TNF-α in autistic children[119]. Singh et al[120] found elevation of IL-2 in autistic children. Elevated inflammatory cytokines and upregulated Th2 and Th17 cells are found to be associated with the development of ADHD and autism.

Autoimmune conditions

There is evidence of abnormal immune response in autism. T cell function response in autism may be more skewed towards a proinflammatory state (Th1 response) which correlates with more severe autism[121,122]. There is also evidence of abnormal cytokine production with increased levels of proinflammatory cytokines such as IL-1β, IL-2, IL-6, IL-8 and IL-12 as well as decreased levels of regulatory cytokines such as IL-10 and TGF-β1, which correlate with more severe symptoms of autism[122,123]. These abnormalities, aside from correlating with the severity of autism, may predispose them to autoimmune conditions.

The above-mentioned abnormalities suggest that autoimmune conditions may be more common in autistic children, with epidemiologic studies looking into the association of rheumatologic and autoimmune conditions and autism having been carried out.

Zerbo et al[124] conducted a case-control study using the Kaiser Permanente database looking for the incidence of autoimmune conditions in autism. This study demonstrated that autoimmune conditions were more common in children, however, this was driven by psoriasis, which was found to occur twice as common as in neurotypical controls. Other autoimmune conditions like juvenile idiopathic arthritis, type 1 DM, and lupus among 41 other autoimmune conditions did not reach statistical significance. A nationwide study from Taiwan using a national health insurance database found that autistic people had a higher incidence of type 1 DM and in general autoimmune conditions as a whole were more common in autistic people. However, this may have been driven by an increased incidence of type 1 DM; other autoimmune conditions did not seem to reach statistical significance[116]. Neither of these studies found a statistical correlation between celiac disease, Crohn’s disease, and autism.

Although not an autoimmune condition, chronic pain syndromes such as fibromyalgia are more common in autistic people. These conditions are characterized by chronic pain in the absence of apparent noxious stimuli. Bursch reported that 20% of the patients with chronic pain followed in the pain clinic at the University of California, Los Angeles had autistic traits[125]. This could be attributed to the neurosensory dysfunction seen in autistic patients, which may increase pain perception. Many of these patients were not diagnosed with autism at the time of evaluation in the pain clinic[111]. Hypermobile joints, which may predispose to chronic pain, have also been found more commonly in autistic children; the same can be said for Ehlers-Danlos syndrome, which is characterized by joint hypermobility, arthralgia, Marfanoid habitus, joint dislocations and hyperextensible skin[126].

Another association between autoimmunity and autism has been found with regard to the risk of autism in children from families with a history of autoimmunity. A meta-analysis found that children from families with a history of autoimmunity had a 28% higher risk of autism. Rheumatoid arthritis, thyroid disorders, and psoriasis were some of the autoimmune conditions included in the studies used in the meta-analysis[127].

Genetic CCs associated with autism

It is essential that the clinician who has diagnosed autism carries out a genetic workup to identify a possible genetic cause. This is important because a known genetic disorder may involve other family members, and this influences future family planning. In addition, many conditions have targeted treatments that can help to reverse the neurobiological changes in the brain and can be implemented for the patient. The recent Food and Drug Administration approval of trofinetide (DayBue) for Rett syndrome is an example of a new targeted treatment. The advent of gene therapy, which is available for Sickle Cell disease and Spinal Muscular Atrophy, is the beginning of a new era of specific genetic therapies that will have a remarkable impact on the field of autism. There are several causes of autism that are undergoing gene therapy trials currently, including Phelan McDermid syndrome, Angelman syndrome, and Rett syndrome with many more to come in the next few years.

The first step in the genetic workup is carrying out microarray testing for finding copy number variants (CNVs) representing about 7 to 8% of autism, and fragile X DNA testing, which causes 2 to 5% of autism. If this first stage testing is negative, then the next step is whole exome sequencing (WES), which has been available since 2009, and whole genome sequencing (WGS) is now currently available, with the cost having improved over time. An exception to this plan is when a phenotypically obvious disorder, such as Down syndrome or Klinefelter syndrome (XXY), is present and instead, chromosomal testing is done to confirm the clinical diagnosis. However, both of these conditions can also be associated with autism, with about 10% of those with Down syndrome, 25% of those with XXY chromosome, and about 30% to 40% of those with XYY chromosome have autism[128].

With microarray testing, sometimes the opposite phenotypic effect is seen between a deletion and duplication at the same location. For instance, 7q11.23 deletion causes Williams syndrome, and these individuals are very social and loquacious and only rarely have autism, whereas a duplication in this same region has a high rate of autism[129]. The deletion and duplication of 16p11.2 both cause autism, but the deletion also causes macrocephaly and obesity, whereas the duplication causes microcephaly and impaired growth[130]. Additional CNVs seen in autism include 1q21.1 deletion and duplication, 15q11.2 deletion and duplication and 22q11.21 duplication and deletion, but each one of these CNVs occurs in less than 1% of those with autism[131].

Fragile X DNA testing utilizes both PCR and Southern blotting, the latter when a full mutation (> 200 CGG repeats) in the FMR1 gene is present. The full mutation causes FXS, the most common inherited cause of ID and single-gene cause of autism, and it occurs in 1 in 4000-5000 in the general population. Those with FXS have a lack or deficiency of the fragile X protein (FMRP), which is a regulator of translation, modulator of many ionic channels, and controller of synaptic plasticity. FMRP regulates the translation of numerous mRNAs, including about 30% of mRNAs from genes associated with autism, so, without FMRP the expression of other genes can be dysregulated[132]. The carrier state, called the premutation (55 to 200 CGG repeats), is typically not associated with ID, but about 15% of the boys and 2%-5% of the girls with the premutation have autism. The premutation is common in the general population (1 in 200 females and 1 in 400 males) and it is associated with elevated levels of FMR1 mRNA (2 to 8 times normal) leading to RNA toxicity. The elevated mRNA levels lead to emotional or psychiatric problems including anxiety, depression, and other neuropsychiatric disorders in about 50%, early menopause before age 40 in 20% and the fragile X-associated tremor ataxia syndrome a neurodegenerative disorder, in 40% of males and 16% of females after age 50[133].

The importance of making the diagnosis of a fragile X mutation relates to the need for genetic counseling/family planning and also the availability of effective targeted treatments including metformin, cannabidiol (CBD), and zatolmilast[134]. The most exciting current targeted treatment for FXS is zatolmilast, which is a phosphodiesterase 4D inhibitor, and this drug inhibits the enzyme that breaks down cAMP, so the level of cAMP (that is too low in FXS) subsequently increases. The increase in cAMP increases the connections and maturity of neurons, and this, in turn increases cognition, language, and reading ability in those with FXS[135].

The use of WES and WGS has identified hundreds of single-nucleotide variants in both the coding part of the genome (WES) and in the noncoding part of the genome (WGS). Such testing has increased the number of genes known to be associated with autism to over 1000[136]. So, the proportion of families with autism who demonstrate a genetic abnormality is about 30% currently with a genetic workup as described above[131]. In some cases, however, there may be multiple common variations that, when combined lead to the phenotype of autism. In addition, environmental factors including toxins and emotional trauma, can affect gene expression through epigenetic changes that do not change the structure of the DNA but silence the expression of some genes[137]. Although there are over 1000 gene variants that are associated with autism, there is molecular convergence, so that the same pathways can be affected by multiple mutations, leading to common treatments that improve more than one disorder. Examples include CBD (cannabidiol) which is efficacious in those with FXS who have > 90% methylation in their full mutation[138] in addition to several forms of autism[139].

NEURODEVELOPMENTAL, MENTAL OR BEHAVIORAL CCS

NDDs are a group of conditions with onset in the developmental period, and they frequently co-occur with autism. According to the fifth edition of the Diagnostic and Statistical manual or mental disorder DSM-5, NDDs are classified as ID, communication disorders, ASD, ADHD, specific learning disorder, motor disorders among other NDDs[1]. For instance, some of the most frequently reported include other developmental diagnosis, intellectual and learning disabilities (LD)[140].

As shown in Figure 3, autistic individuals have a markedly increased risk of psychiatric CCs compared to neurotypical controls. The most identified neuropsychiatric CCs include ADHD, anxiety disorders and depression, occurring at significantly higher rates than the general population[141]. These CCs can be often experienced by autistic people from childhood to adulthood[142]. Psychiatric symptoms can be experienced and expressed by autistic individuals in varied clinical presentations.

Figure 3 Forest plot of hazard ratios and 95%CIs for the risk of developing subsequent psychiatric co-occurring conditions in autism compared to neurotypical controls. The plot includes estimates for children, adolescents, and the overall autism population across five psychiatric conditions: Anxiety disorder, obsessive-compulsive disorder, schizophrenia, bipolar disorder, and depressive disorder. Hazard ratios (HRs) greater than 1 indicate an increased risk of developing the disorder in the autism group compared to neurotypical controls. The dotted vertical line represents an HR of 1, indicating no difference in risk between autism and neurotypical controls. All results are statistically significant with a P < 0.05, indicating that the increased risks observed are unlikely due to chance. Error bars reflect the variability in the estimates, with wider intervals indicating greater uncertainty. CCs: Co-occurring condition; HR: Hazard ratio; OCD: Obsessive compulsive disorder.

There is mixed evidence supporting the level of autism symptom severity as a predictor of mental health conditions. As a general rule, the onset of new behaviors or changes in the daily functioning of autistic people should alert clinicians about the possibility of an underlying psychiatric CCs which can become challenging due to the diversity of presentations and diagnostic overshadowing. Moreover, these mental health CCs can influence the clinical presentation of autism enhancing or mitigating associated challenges. Existing literature also suggest different presentation based on age and gender. For instance, anxiety symptoms have been reported to increase in adolescence with a decrease noted during adulthood, while diagnoses such as schizophrenia increased by age affecting largely male individuals[143-145].

The most commonly associated anxiety disorders are social anxiety disorder, generalized anxiety disorder and specific phobia[146]. Clinically, anxiety and autism symptoms may overlap, and sometimes it is not very clear whether those behaviors are driven by anxiety or the core symptoms of autism (i.e., fear of loud noises or distress due to changes in routine). Moreover, other characteristics including challenges in communication, variability processing sensory experiences including their own sense of physiological states (interoception), and alexithymia has been reported in nearly half of the people with autism[147]. There is some evidence supporting the emergence of anxiety symptoms even in younger children, especially in females[148].

Similarly, obsessive-compulsive disorder (OCD) has been more frequently identified in autistic people. This mental health condition is characterized by persistent, unwanted thoughts (obsessions), and consequent repetitive behaviors or mental rituals (compulsions) that an individual feels driven to perform to alleviate the distress from obsessions. Differentiating these from core autistic characteristics can be challenging as autistic people frequently experience strong interests and repetitive behaviors. However, in OCD, these repetitive actions are accompanied by distress while repetitive actions in people with ASD (i.e., flapping hands, jumping or pacing) usually do not cause distress and they frequently play a self-regulatory role. This clinical presentations can be a challenge for clinicians because autistic individuals can spend long periods engaging in repetitive behaviors, and distress can be frequently observed when interrupted or commanded to stop this behavior. Individuals with OCD can also experience a range of emotional responses complicating the differential diagnosis even further[1]. In autism, the repetitive patterns of behaviors usually start early in life while OCD is usually diagnosed later in life with a mean onset of 19.5 years, although, males tend to have an earlier onset.

The most frequently observed mood disorder is major depressive disorder (MDD) reported about in 11% of this population which is significantly higher than in the general population about 7%[149]. MDD is characterized by persistent sadness or depressed mood, accompanied by somatic or cognitive symptoms affecting their daily functioning[1]. MDD has been more frequently found in people with ID.

It has been found that some factors may predispose autistic individuals in a more vulnerable position for depressive symptoms. For instance, social challenges can be associated with isolation, coping with sensory sensitivities may increase distress, and other CCs have been postulated as risks factors. In a longitudinal study it was found that depressive symptoms tend to increase through adolescence in females, with no sex differences later in life[150]. It has also been reported that the prevalence of depressive symptoms is higher in the autistic population with higher IQ compared to those with ID[151]. The expression of depressive symptoms can widely vary from classic presentations like anhedonia, feeling guilty and suicidal ideation, to presentations with increased externalizing symptoms including irritability and aggression. Social withdrawal, increased sensory sensitivity, loss of interest in favorite topics or changes in appetite or sleep pattern should alert clinicians about the presence of a mood disorder. In non-verbal individuals, depression symptoms can be experienced by changes in communication, loss of eye contact, physical complaints or self-injurious behaviors[152].

The first treatment for mood issues includes cognitive behavioral therapy adapted for this population. This is an evidence-based intervention that not only targets anxiety and depression but is also beneficial in increasing the understanding and interpretation of social cues more effectively by targeting specific social skills. It can increase self-awareness, improve emotion regulation, and enhance perspective-taking abilities, which are critical for social functioning.

The disruptive mood dysregulation disorder (DMDD) is a mood disorder characterized by severe temper outbursts that are out of proportion to the situation. While DMDD is primarily diagnosed in children and is not specific to autism, there are important connections between the two and symptoms may overlap. In the context of autism, individuals might exhibit behaviors that overlap with those seen in DMDD, such as irritability, mood swings, and difficulty regulating emotions[153,154]. However, the underlying causes and treatment approaches might differ. In general, treatment in autistic children and teenagers typically involves behavioral interventions, speech therapy to promote effective communication, occupational therapy, and sensory integration approaches to help manage emotional regulation. Usually, the diagnosis should be performed by a mental health provider with extensive experience in both diagnoses.

Mood issues can also present with catatonia which is a neuropsychiatric syndrome that involves a variety of motor and behavioral abnormalities, such as immobility, mutism, and excessive movement or agitation. It has been increasingly recognized in autistic individuals, though it is often underdiagnosed or misinterpreted due to the overlap of catatonic symptoms with core features of autism. It has been reported that catatonia can occur in approximately 10% to 20% of autistic people. Although catatonia can occur in the context of several disorders, the DSM-5 diagnostic criteria for Catatonic Disorder have not been tailored to autistic people and the unique behavioral patterns often seen in this population leads to lack of identification and treatment.

The pathophysiology of catatonia in autism is not fully understood, but it is thought to involve dysfunction in the dopaminergic system, GABAergic neurotransmission, and possibly NMDA receptors. Alterations in these pathways have been reported altered in this population, making them more susceptible to catatonic episodes, particularly during periods of stress, anxiety, or sensory overload[155]. Pharmacological treatments are usually utilized when psychotherapy has no yielded benefit.

Although there is no one-size-fits-all approach, various medications have been studied for their efficacy in treating these conditions in autistic individuals. Several medications have shown effectiveness in treating anxiety and depressive symptoms such as SSRIs, selective norepinephrine reuptake inhibitors, and atypical antipsychotics when symptoms of mood irritability, aggression and property damage are present.

Psychopharmacological treatments should be closely monitored, with risks and potential benefits taken into consideration and starting at low doses and with slow up-titration[156].

An estimated 5%-15% of school-aged children struggle with a LD[157]. It has long been understood that autism impacts learning, particularly among more severely affected individuals[158]. Complicating our understanding of the co-occurrence, however, is the overlap of studies that examine LD defined in part by an ID in the context of autism. Several articles go so far as to define LD in the context of low IQ[158,159], and researchers have argued that the cognitive heterogeneity of autistic children makes it difficult to characterize academic difficulties of this population[160]. The DSM 5-TR typically excludes individuals with ID from the LD definition given different intervention needs and the explicit exclusion of learning not better accounted for by ID in particular. The current definition of LD refers to difficulties learning and using academic skills despite the provision of interventions that target those difficulties[51]. Studies that examine academic performance of autistic students have generally found variable performance consistent with the heterogeneity of autism itself[161]. As a result, studies look to categorize differences in learning across categories including high/Low achievement and/or specific areas of strength in math calculation and reading decoding[162,163].

Reading disability, commonly referred to as dyslexia, is the most common specific LD with 80% of students with LD struggling with reading in particular[164]. Studies have linked common challenges among dyslexia and autism, including struggles with visual processing that cuts across both groups[165]. With regard to specific challenges with reading, studies have largely shown that for those autistic children but without ID, strengths are noted in their ability to decode words relative to their reading comprehension. Still, there is marked heterogeneity noted across studies with various learning profiles explored (i.e., those with decoding challenges alone, those with decoding challenges and reading comprehension challenges, etc.)[166].

Writing disability, or dysgraphia impacts a students’ ability to write. In a study examining autistic children and adolescents and variable intelligence, approximately 60% of students struggled in this area of learning[167]. Automaticity in writing remains a crucial component for academic achievement and studies have recommended the use of tablets or other supports to aid in writing for children who struggle in this area[168].

Challenges with mathematics, or dyscalculia, impacts children’s abilities with mathematical problem solving, fluency and calculation skills. While studies have historically been mixed with regard to mathematical abilities in autistic children, a recent meta-analysis highlighted that autistic people tend to have poorer math skills than their typically developing peers and that this was moderated by factors such as verbal intellectual functioning and working memory capabilities[169].

The prevalence and heterogeneity of learning differences that co-occur with autism underscores the need for clinicians and academic institutions alike to not only prioritize the social communication and behavioral needs of children, but to design approaches that enhance and support academic achievement.

ID is characterized by delayed intellectual functioning and adaptive skills observed during development (prior to age 18). It is typically assessed through a combination of standardized testing (i.e., IQ tests) and clinical assessment of adaptive skills (i.e., self-care, communication and social skills). While estimates note the prevalence of ID in the general population range between 1%-2% of the population[170], co-occurrence with autism is much more common. Specifically, studies report rates of near 10% of children with ID have co-occurring diagnosis of autism[171] and recent data from the CDC estimates that autistic children are found to have co-occurring ID (IQ ≤ 70) at a rate of 38%, with rates generally decreasing over time[172]. The distribution by intellectual ability varied by sex, with girls more likely than boys to have IQ ≤ 70. Common genetic pathways have been identified across autistic and ID populations[171]. In addition, unique phenotypes have emerged with co-occurring comorbid challenges. For example, those with lower IQ and autism, have been shown to have significantly higher rates of stereotyped and more challenging behavior; specifically self-injurious behaviors[173]. These also tend to persist as those with autism and ID age into adulthood[174]. The presence of ID with autism is also generally associated with poorer long-term prognosis and reduction in functional independence when compared to individuals with ID alone[175,176]. This highlights the ongoing need for intervention and support services tailored and adapted to this specific population.

Beside an accompanying ID specifier, autistic people often present with an uneven profile which can be associated to unique strengths and challenges[1].

Similarly, the use of the specifier “with or without language impairment” may include a wide variation of skills at the moment of the diagnosis and it is expected to change over time.

Ear, nose and throat CCs

Longitudinal birth cohort studies, retrospective case-cohort studies, and parental reports suggest an increased risk of otitis media in autistic children compared to children with neurotypical development[177-182]. Potential causes include craniofacial abnormalities (low-set ears), environmental exposure (such as tobacco and daycare), eustachian tube dysfunction, sleep-disordered breathing, obstructive sleep apnea and gastroesophageal reflux, low uptake of pneumococcal and influenza vaccines[183-186]. Recurrent otitis media in autism has a disproportionately significant impact on quality of life with delays in speech and language development, school performance, reading and cognitive ability, and inattentive or hyperactive behaviors, which could compound underlying difficulties in autism[187-190]. Otitis media should be considered in presence of fever or behavioral changes such as new-onset aggression, tantrums, or self-injurious behavior, as these may mask pain from the underlying condition to prevent delay in diagnosis and complications[181]. Tympanometry is often recommended over pneumatic otoscopy for these evaluations, as it is generally better tolerated by autistic children and provides a printed result for reference[191].

Rates of tympanostomy tube (TT) placement are also higher in autism compared to neurotypical controls[181,192,193]. According to the clinical practice guidelines for TT in children by the American Academy of Otolaryngology–Head and Neck Surgery Foundation, those at increased risk for developmental delays can have TT insertion with unilateral otitis media with effusion (OME) or without apparent hearing difficulties[191]. Future studies should investigate whether this approach leads to meaningful improvements in developmental outcomes in autism. This would help to quantify the real-world developmental impact, avoid unnecessary interventions and personalize care based on individual benefit. Another future area of research would be investigating how frequently ear, nose, and throat (ENT) providers screen autistic children for OME using tympanometry or refer them for audiological assessments. It would also be valuable to examine the clinical thresholds used to recommend TT placement in this population, particularly in light of the communication challenges and atypical symptom presentations that may delay diagnosis.

Autism is associated with various sensory processing abnormalities, including decreased sound tolerance (DST), which encompasses conditions such as hyperacusis, misophonia, and phonophobia. Misophonia is characterized by intense emotional reactions to specific sounds, such as chewing or breathing, and is prevalent in this population. It often co-occurs with psychiatric comorbidities like anxiety, OCD, and depression[194-196]. Phonophobia, defined as a specific phobia of sound, is another aspect of DST that can be observed in autistic individuals. Hyperacusis is characterized by an increased sensitivity to normal environmental sounds. Hyperacusis can lead to significant distress and functional impairment, thereby affecting social interactions and daily activities[197].

Autistic children have a higher prevalence of hearing impairments (conductive and sensorineural hearing loss) compared to the general population[198,199]. Hearing loss can delay autism diagnosis and also compound language development and social skills[200,201]. Autism should be considered as a concurrent diagnosis in children presenting with profound hearing loss under three years[202]. Cochlear implantation is typically recommended for children with profound hearing loss by age 1 to optimize auditory and language development. However, autism is often diagnosed later, typically around age 3, which can complicate the decision-making process for cochlear implantation. Studies have shown improvements in auditory skills, language development, and social engagement following cochlear implantation in autistic children, although outcomes can be highly variable[203-205].

There is growing interest in sensory-friendly ENT care, as procedures such as otoscopy and audiometry can be uncomfortable for autistic children. Fahy et al[206] conducted a mixed-methods study to explore how peri-operative care for autistic children undergoing ENT procedures could be improved[206]. The study aimed to identify psychosocial challenges these children face in clinical settings - such as sensory sensitivities, communication difficulties, and anxiety triggered by unfamiliar environments. The authors emphasized the need for individualized care, recognizing parents as key partners in planning, and advocated for strategies like social stories (visual and narrative guides that familiarize children with hospital routines and settings), hospital passports (documents completed by caregivers outlining the child’s preferences, sensitivities, and communication needs), and environmental modifications to reduce distress (such as quiet waiting areas, visual schedules, reduced transitions, and clear, low-arousal communication techniques). Based on their findings, they developed a local social story tool to support autistic children during hospital visits.

Ophthalmological CCs

Autism is associated with a range of ophthalmological CCs, as evidenced by several studies in the medical literature. A systematic review and meta-analysis has shown that autistic individuals have a higher prevalence of strabismus, accommodation deficits, reduced peripheral vision, reduced stereoacuity, color discrimination difficulties, reduced contrast sensitivity, and increased retinal thickness[207]. CP is a significant risk factor for the development of refractive errors, strabismus, amblyopia and optic neuropathy in autism[208]. Several genetic syndromes are known to be associated with both autism and specific eye disorders. Notably, FXS is associated with high rates of strabismus, Williams syndrome with distinctive almond-shaped eyes and classic stellate iris presentation, Angelman Syndrome with choroidal and iris hypopigmentation, and CHARGE syndrome with colobomas[209-212]. There is also a strong association between congenital blindness and an increased risk of autism, with conditions like retinopathy of prematurity, Leber's amaurosis, and septo-optic nerve dysplasia being linked to autism[213-215].

Strabismus is one of the most frequently reported eye disorders in autism. Both exotropia (outward turning) and esotropia (inward turning) occur, with studies varying in the prevalence of these conditions[216,217]. Uncorrected strabismus can lead to impaired depth perception and binocular vision, and may contribute to social difficulties (e.g., reduced eye contact). Untreated strabismus is a significant risk factor for developing amblyopia. Strabismus is associated with increased odds of developing ADHD and anxiety disorder in children[218]. Early detection and intervention are crucial to prevent the development of amblyopia and also to enhance social well-being and potential psychosocial consequences as well.

Refractive errors such as anisometropia, astigmatism, and hypermetropia have been found to be more common in autism compared to the general population[219,220]. Uncorrected refractive errors can exacerbate learning and communication challenges by limiting clear vision. Due to the high rates of strabismus and refractive error, amblyopia (functional vision loss in one eye from disuse during development) is also more frequent in this population[208,215].

Other less common but important ophthalmological CCs include optic neuropathy, nystagmus, and retinal diseases. Optic neuropathy involves damage to the optic nerve and can lead to vision loss. A small subset of autistic children has structural eye findings like optic nerve hypoplasia (underdevelopment of the optic nerve) or retinal abnormalities (retinal detachment)[221,222]. Involuntary oscillation of the eyes (nystagmus) is relatively uncommon but does occur in some autistic individuals. The vestibulo-ocular reflex (VOR) function, which is related to nystagmus, has been studied in high-functioning autism children. Alterations in VOR, such as increased gain and irregular nystagmus patterns, suggest potential cerebellar and brainstem circuitry differences in autism[223]. Oculomotor disturbances, including gaze fixation abnormalities and atypical saccades are well-documented in autistic individuals[224]. Gaze fixation abnormalities are characterized by difficulties in maintaining stable fixation[225]. These fixation issues can contribute to challenges in processing visual information, particularly in social contexts, where stable gaze is crucial for interpreting facial expressions and engaging in joint attention. Atypical saccades are marked by saccade dysmetria and faster but less precise saccades, hinder exploratory behaviors and lead to difficulties in social situations[226,227].

Standard vision screening or exam techniques rely on cooperation and communication, which can be difficult for some autistic individuals due to developmental and sensory differences. Autistic children are significantly less likely than their neurotypical peers to receive vision screening during well visits[228,229]. Instrument-based vision screening methods, such as photoscreening and autorefraction, are useful alternatives to traditional visual acuity tests as they minimize the need for verbal instruction and active participation[230]. A study by Parmar et al[231] explored barriers faced by autistic adults during eye examinations. Autism-friendly eye care should include nonverbal booking options, clear explanations of each test, reduced sensory triggers, and continuity with the same provider. Providing visual “what to expect” materials and allowing breaks or patient control over equipment can ease anxiety and improve the overall experience.

Cardiometabolic conditions

There is growing recognition of a significant link between autism and an increased risk of developing cardiometabolic diseases compared to the general population. Figure 4 summarizes pooled relative risks for metabolic and cardiovascular comorbidities in autism. A systematic review and meta-analysis published in JAMA Pediatrics highlights that autistic individuals are at a higher risk for several cardiometabolic conditions, including diabetes, dyslipidemia, and heart disease[232]. However, the study did not find a significant association between autism and hypertension or stroke. Another study explored the prevalence of obesity and hypertension in autistic adults, indicating a high prevalence of overweight and obesity, consistent with rates in the general United States population. ID was associated with a lower body mass index, but not with hypertension[233]. A bidirectional relationship exists between type 2 diabetes and autism. A Mendelian randomization study indicated that type 2 diabetes increases the risk of autism, and conversely, autism increases the risk of type 2 diabetes, suggesting a potential intergenerational risk cycle[234]. This is explained through mechanisms involving neuronal network hyperexcitability[235].

Figure 4 Forest plot of relative risks and 95%CIs for metabolic and cardiovascular conditions among autistic patients compared to neurotypical controls. The plot presents pooled relative risk (RRs) from meta-analyses across multiple studies for various conditions: Diabetes overall, type 1 diabetes, type 2 diabetes, dyslipidemia, heart disease, hypertension, and stroke. Blue points indicate significant associations (P < 0.05), where the 95%CI does not cross the line of no effect (RR = 1), suggesting a higher risk of the condition in autistic individuals compared to controls. Red points represent non-significant results (P ≥ 0.05), where the 95%CI crosses the RR = 1 line, indicating no statistically significant difference in risk between autism and controls. The vertical dashed line at RR = 1 serves as a reference, representing no increased or decreased risk. Conditions such as type 2 diabetes and dyslipidemia show a notably higher risk in autism, while the risk differences for hypertension and stroke are not statistically significant.

However, the cause of obesity in this population is multifactorial, involving a genetic, behavioral, and environmental factors. Several etiological factors have been proposed, including genetic variants (e.g., 16p11.2 deletion), prenatal exposures to infections or medications, maternal diabetes, and maternal obesity[236]. Behavioral factors also play a significant role. Autistic children often exhibit atypical eating behaviors, such as food selectivity, which can lead to an imbalanced diet high in energy-dense foods and low in essential nutrients[237]. Additionally, physical activity levels are generally lower in these children due to motor impairments, social challenges, and limited opportunities for physical engagement[238]. Medication use, particularly antipsychotics, is another contributing factor. These medications, commonly prescribed to manage behavioral issues in autism, but are associated with weight gain. The strong association between these medications and obesity/diabetes risk highlights the importance of careful consideration of medication choices and diligent metabolic monitoring for autistic individuals. Sleep disturbances, which are prevalent in these children, can further exacerbate weight gain by disrupting metabolic processes[239]. Studies have shown that autistic individuals often have altered lipid profiles, including higher levels of triglycerides and lower levels of high-density lipoprotein cholesterol[240]. These lipid abnormalities can contribute to the development of cardiovascular diseases. A Mendelian randomization study indicated causal relationships between autism and various cardiovascular conditions, including stroke, ischemic stroke, large-artery atherosclerotic stroke, atrial fibrillation, and heart failure[241].

Autism has been associated with reduced life expectancy and an increased risk of premature mortality, with circulatory causes contributing significantly to this trend. A study by Smith DaWalt et al[242] reported that autistic individuals have higher rates of health problems, including chronic conditions like heart disease, which contribute to early mortality. A systematic review by Catalá-López et al[243] confirmed that autism is associated with a significantly increased risk of all-cause mortality, with deaths from natural causes, including cardiovascular diseases, being notably higher in this population. Given the increased prevalence of cardiometabolic diseases in this population, it is likely that these conditions contribute to the higher mortality rates observed, underscoring the critical need for effective prevention and management strategies. Early screening and tailored interventions can help reduce the long-term burden of obesity-related conditions, ultimately improving quality of life and longevity for individuals on the autism spectrum.

Limitations of the literature

Our narrative review draws upon extensive literature on CCs in autism. Inherent limitations in the individual studies cited warrant careful consideration when interpreting the findings. The inconsistency in prevalence rates across studies is multifactorial, relating to heterogeneity in study design, population characteristics, diagnostic inconsistency and evolving criteria, lack of longitudinal follow-up, and lack of adjustment for moderators/confounders.

Studies to determine prevalence of CCs in autism are heterogenous including prospective cohort studies, clinic-based samples, retrospective chart-based reviews, administrative databases and cross-sectional studies. For instance, the prevalence of GI CCs ranges from 4.2%-96.8% across studies[90]. Differences in prevalence rates are also observed in ADHD, anxiety, and sleep disturbances. Retrospective chart reviews and administrative databases may underestimate CCs due to inconsistent reporting, lack of direct clinical assessment, missing data and data quality issues. Also, retrospective or cross-sectional studies cannot infer causality or the directionality of associations in understanding whether CCs precede, result from, or simply coexist with autism. Moreover, clinic-based samples may overestimate CCs due to referral bias and greater severity of cases seen in specialty clinics. Prospective cohort studies are limited by strict inclusion criteria and attrition, which may limit direct comparison across studies. Self- or parent-reported questionnaires are affected by systematic biases related to recall and reporting, and this has been shown to influence prevalence estimates, such as higher psychiatric CCs[145,179,244-247].

Moreover, population characteristics limit inter-study comparison. Studies that have deployed large sample sizes (SPARK database, Swedish twin study) have higher statistical power and better generalizability[11,12]. This is in contrast to smaller clinic-based studies or retrospective chart reviews limited to a single center. Study populations are often drawn from a specific region or health system (e.g. Olmsted County, Minnesota or United States insurance databases)[248,249]. This may limit generalizability across countries, socioeconomic groups and healthcare systems.

The evolving diagnostic landscape and increased awareness of autism has led to changes in case identification and CCs’ recognition over time. Use of ICD codes or DSM criteria leads to divergent prevalence rates as opposed to clinic-based assessment or use of standardized instruments[248,249]. The umbrella of cases under autism also differs across time due to changes in diagnostic criteria, recognition of milder forms of autism, or presence of communication difficulties and atypical symptom presentations complicating the identification and assessment of CCs. Therefore, comparison across decades must be interpreted with caution. In addition, studies may not account for the effect of modifiers and confounders such as age, gender, body-mass index, use of psychotropic medications, autism severity and ID[232,250,251]. This would affect the causal relationship between autism and CCs as anxiety, ADHD are more common in younger children, in contrast to, depression and schizophrenia, which emerge later in adolescence and adulthood[252]. Similarly, differences in CCs also vary by gender[252]. The presence or absence of ID substantially alters the observed rate of medical and psychiatric CCs[252]. There is a paucity of data on CCs in middle-aged and older adults that limit our understanding of the trajectory across the lifespan. Most studies focus on children, and findings may not extrapolate to adult populations[253]. Lack of longitudinal follow-up represents a major gap, and longitudinal tracking would help bolster the temporal relationship between CCs and autism, particularly whether CCs are transient, persistent or exacerbated by developmental trajectories.

Differences in outcome definitions and data collection tools further complicate interpretation. GI symptoms are variably defined across studies – some use parental reports of “frequent diarrhea”, others requiring clinical diagnosis or using stool consistency scales[90]. Similarly, with identification of sleep problems, some studies utilized polysomnography, while others used caregiver-reported questionnaires[254]. The lack of granularity in case definitions can also affect the results, with some studies not differentiating between conditions (for e.g., type 1 or type 2 diabetes) or use broad diagnostic categories that limit the estimation of specific disorders[232].

Finally, the underlying etiological relationship between autism and CCs contributes to variability. CCs may share genetic risk with autism or may be an independent co-occurrence[255]. The overlap in symptomatology between autism and psychiatric CCs (anxiety, psychosis) can complicate diagnosis and prevalence estimates[15,256]. Few studies account for interactions between CCs, such as how sleep disturbances aggravate behavioral or mood symptoms, or how GI discomfort manifests as externalizing behaviors.

By acknowledging these limitations, future research would improve the reliability and translatability of research on autism and CCs to support better-informed clinical decision making.

CONCLUSION

Autistic individuals are frequently reported to experience CCs that affect their daily functioning and well-being. The presence of CCs can also influence the heterogeneity and complexity of autism diagnosis, and the expression of autistic features over time. For instance, these accompanying conditions may influence the clinical presentation and therapeutic approaches described in detail by this panel of experts.

Autism is frequently associated with other NDDs including developmental issues including speech and motor delays that can affect their access to therapeutic interventions. The presence of other NDDs can be identified later in life but can equally influence the individual’s management, some include ADHD, learning difficulties, ID and motor disorders, which can have a negative impact on academic achievement, school success and self-image.

In general, associated medical and mental health CCs are frequently underidentified and misdiagnosed. Challenges experienced by autistic people can negatively impact their timely diagnosis and management due to communication challenges, variability in sensory experiences, and atypical presentations, however, PCPs and specialist caring for autistic people should be familiar with these common issues and possible presentations.

Although there is a great variability in implicated systems, some of the most common diagnoses include neurological problems, GI symptoms, sleep disturbances, sensory challenges, motor issues, and mental health problems. Other common physical health problems are also frequently reported in autism such as ear infections, dental caries, etc., can present as behavioral issues, self-injurious behaviors or changes in daily functioning. Moreover, autistic individuals are at increased risk for cardiovascular health issues, which should be monitored from an early age - particularly in those with restrictive eating patterns, exposure to medication side effects, and reduced physical activity, all of which may contribute to long-term adverse outcomes. Mental health diagnoses are also commonly experienced by autistic patients including anxiety, depression and irritability. Although these conditions are common, they are not explained solely by an autism diagnosis and in general terms, autistic people should have access at the same level of care as neurotypical individuals. The prevalence of these accompanying diagnoses can vary over time, consequently, screening and evaluating for other CCs should happen longitudinally to promote early access to the right care and hopefully positively impact long term outcomes for this population.

Integrated care models promote coordinated, holistic care for autistic individuals by addressing their full spectrum of needs - medical, psychological, educational, and social-within a comprehensive framework. These models should aim to break down silos between different healthcare and service providers to ensure that the autistic person receives cohesive, individualized support across various domains. Early diagnosis, intervention, and continuous care coordination are essential to help autistic individuals thrive across all aspects of their life.