POLSKI
Introduction
Autism spectrum disorder (ASD) encompasses a wide continuum of associated cognitive and neurobehavioral features, including the main ones of an impaired socialisation, impaired verbal and nonverbal communication, and restricted or repetitive patterns of behaviour [1]. Kanner’s autism, reported for the first time in 1943, was easy to describe due to reported symptoms of an intense clinical expression [2]. In 1980, in the Diagnostic and Statistical Manual (DSM-III) classification of Mental Disorder, autism was recognised for the first time as a separate entity and was placed into the group of pervasive developmental disorders (PDD) [2]. The current American DSM-V classification established a single category of autism spectrum disorders (ASD) to replace all the subtypes of autism, Asperger’s syndrome, and PDD [3, 4]. The term “spectrum” represents the variability in severity of symptoms. Expanding its definition to include more subtle features has made them more difficult to categorise and may be the reason for the overdiagnosis of autism [3, 4]. However, any neurodevelopmental condition combined with some degree of intellectual disability (ID) and behavioural problems has also been shown to increase the likelihood of meeting certain criteria for ASD [5].
Inherited metabolic diseases (IMD), known also as inborn errors of metabolism, represent a group of genetic conditions related to the alteration of various biochemical pathways. The current (2021 year) classification includes 1,450 disorders divided in 24 categories comprising 124 groups [6]. The clinical and biochemical phenotype of IMD is quite heterogeneous, reflecting, for example, the complexity of their pathomechanism. Both, exome and genome sequencing technologies have revolutionised molecular diagnostics, allowing the identification of new disease entities among IMD as well as the characterisation of new phenotypes for already described diseases [6]. There is also a growing number of reports on ASD/autistic features, as one of the presenting symptoms of IMD [7].
Given the increasing prevalence and knowledge of ASD and IMD, both separately and co-occurring, the aim of this manuscript was to provide practical implications of the molecular (metabolic) diagnosis of ASD and also give the rationale of selective screening of IMD in paediatric patients presenting with ASD.
Autism spectrum disorder clinical heterogeneity and diagnostic implications
A wide range of diagnostic tools have been developed, while both the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised are considered the gold standard for diagnosing ASD [5].
The diagnostic process of a child with ASD should start with a detailed family history (with emphasis on individuals with ASD, psychiatric, or neurologic disorders) and physical examination (including dysmorphology, growth parameters – including head circumference, neurological examination) [1, 7]. The clinical diagnosis of ASD may be complicated by the overlap of different phenotypes, especially including intellectual disability, or epilepsy [1, 7].
Genetic studies
The dynamic development of various molecular biology techniques has made ASD the subject of intensive research on the genetic basis. The American College of Medical Genetics and Genomics (ACMG) recommends that a genetic consultation should be offered to all persons/families with ASD [8].
The 2010 guideline from the ACMG suggested that chromosome microarray (CMA) and fragile X (FXS) testing should be first-tier tests for individuals with ASD (except for females with ASD and normal cognition) [9, 10]. Chromosomal defects associated with ASD include Turner (45, X), Down (trisomy 21), Williams (chromosome 7q11.2 deletion), Smith-Magenis (17p11.2 deletion), and Phelan-McDermid (22q13 deletion) syndromes [11].
More recently, next-generation sequencing (NGS)-based CNV analysis is being increasingly used in clinical testing through gene panel, exome, and genome sequencing [11, 12]. Monogenic disorders with well-defined autism include Fragile X syndrome (FMR1 gene), Rett syndrome (MECP2 gene), tuberous sclerosis (TSC1 and TSC2 genes), and neurofibromatosis (NF1 and NF2 genes) [12]. Other syndromic conditions associated with autism include Sotos, Moebius, Cohen, De Lange, and Joubert syndromes [12].
Both genome-wide association studies and genetic linkage analysis have identified hundreds of DNA polymorphisms clustered in ASD risk gene loci recognised on all chromosomes and within the human genome, consisting of around 20,000 genes [13, 14]. Also, a 2019 meta-analysis demonstrated that clinical exome sequencing outperforms CMA as a first-tier diagnostic test for individuals with neurodevelopmental disorders or ASD [15]. According with the latest AMCG guidelines (2021 year), exome and genome sequencing are recommended as a first-tier or second-tier test (guided by clinical judgment and often clinician-patient/family shared decision making after CMA or focused testing) for patients with developmental delay (DD) or intellectual disability (ID) with onset prior to age 18 years [16].
Metabolic studies
A wide range of autistic features have been reported in patients with various IMD, including aminoacidopathies, organic acidurias, cerebral creatine deficiencies, and defects of purines and pyrimidines metabolism, see Table I [7, 17–19]. Regarding their clinical presentation, it is worth underlining that autistic features do not constitute the leading or the only presenting symptom of IMD, which often includes multi-organ involvement (Table II). In all reported IMD, autistic features/behaviours are secondary to the delayed psychomotor development and/or intellectual disability [7, 17–19].
Table I
Inherited metabolic diseases with reported autistic features
Table II
Cross-sectional studies reporting children diagnosed with ASD who were subsequently screened for IMD
| Type of study/number of patients with ASD | Percentage of positive IMD screening | Factors/features associated with positive IMD screening | IMD identified in the study | References |
|---|---|---|---|---|
| Multicentre study in Iran; 105 children and adolescents with ASD | 13/105 (12.4%) | Consanguinity 7/13 Epilepsy 4/13 Delayed psychomotor development 7/13 Positive family history of IMD 0/13 | Cerebral creatine deficiency syndrome, arginosuccinate lyase deficiency, 2-methylbutyryl glycinuria, short-chain acyl-CoA dehydrogenase deficiency, guanidinoacetate methyltransferase deficiency, combined methylmalonic and malonic aciduria | [20] |
| 320 children diagnosed with ASD followed up in the Paediatric Neurology Clinic, Menoufia University Hospitals | 8/320 (2.5%) | Consanguinity 5/8 Epilepsy 4/8 Mental retardation 4/8 Positive family history of IMD 1/8 | Phenylketonuria, glutaric aciduria type 1 | [21] |
| 274 children aged 2–17 years hospitalized at the Robert Debré University Hospital (Paris, France) | 2/274 | Mental retardation 1/2 | 3-methylglutaconic aciduria, elevated creatine urinary excretion – no pathogenic variant in genetic analyses | [22] |
| 237 patients were evaluated for IEM leading to ASDs | 6/237 (2.5%) | Consanguinity 2/6 Mental retardation 3/6 | Phenylketonuria (PKU), cerebral creatine deficiency, hypobetalipoproteinaemia, glycogen storage disease type IXa, dihydropyrimidine dehydrogenase deficiency, succinic semialdehyde dehydrogenase deficiency | [23] |
| 277 autistic children | 14/277 (5.1%) | n.a. | Phenylketonuria, homocysteinaemia, propionaemia, methylmalonic acidaemia, glutaric acidaemia, isovaleric acidaemia, argininemia, citrullinemia I, primary carnitine deficiency | [24] |
| 222 children with ASD referred to a tertiary university Neurodevelopmental Centre in Northern Greece | 6/222 (2.7%) | n.a. | Mucopolysaccharidosis type III, hypothyroidism, L-2-hydroxy-glutaric aciduria, vitamin B6 deficiency and seizures, phenylketonuria | [25] |
| 187 children with ASD aged 4–14 years | 5/187 (2.7%) | n.a. | Lesch-Nyhan syndrome, succinic semialdehyde dehydrogenase (SSADH) deficiency, phenylketonuria | [26] |
| 300 patients with ASDs admitted to the Cerrahpasa Medical Faculty Paediatric Nutrition and Metabolic Disorders Clinic | 9/300 (3%) | Consanguinity 5/0 Mental retardation 7/9 | Mucopolysaccharidosis type III, L-2-hydroxyglutaric aciduria, partial biotinidase deficiency, short chain acyl-coA deficiency (SCADD); classical HCY, glutaric aciduria type 1, argininaemia, phenylketonuria (PKU) | [27] |
| 406 patients (age range 3–22 years) with non-syndromic ASD screened for IMD in Spanish multicentre study | 0 | No diagnoses of IMD | No diagnoses of IMD | [28] |
To assess the reasonability of selective screening into IMD in patients with autistic features/behaviours, a search was conducted in PubMed on cross-sectional studies reporting children diagnosed with ASD who were subsequently screened for IMD. Nine studies were identified (Table II) with a percentage of positive IMD screening ranging from 0 to 12.4% [20–28]. It should be noted that the clinical phenotype of autistic patients diagnosed with IMD was not characterised in detail. However, the Authors found an association between ASD in IMD and parental consanguinity, epilepsy, and delayed psychomotor development/intellectual disability [20–28]. Most authors concluded that a routine metabolic screening does not contribute to the causative diagnosis of non-syndromic ASD. Schiff et al. also emphasised that the prevalence of screened IMD in non-syndromic ASD is probably not higher than in the general population (< 0.5%) [22].
The most common inborn error of metabolism identified in ASD patients was phenylketonuria (PKU). The association between PKU and ASD is very well documented. Autistic features are being developed secondary to severe intellectual disability. However, during the last 20 years, the prevalence rate of ASD in phenylketonuria dramatically dropped owing to an early detection (via newborn screening) and treatment of phenylketonuria [29].
Discussion
The heterogeneity of clinical expression and severity of symptoms reported in IMD as well as the possibility of causative treatment in some cases, forces the diagnosis to be made as soon as possible [30]. Therefore, the principle of selective screening applies in the diagnostics of IMD. If the symptom/cluster of symptoms suggests a (known) inborn metabolic disease, diagnostic tests should be performed – not just to confirm the suspicion, but also to exclude it. Although most reported papers proposed metabolic (IMD) screening in patients with ASD associated with other abnormalities [31], especially parental consanguinity, developmental delay/intellectual disability, and epilepsy, there is a growing number of papers suggesting metabolic screening in all patients with ASD. However, a systematic metabolic work-up is not contributive to the aetiology of non-syndromic ASD (isolated autism) [22]. On the other hand, regarding genetic consultation, the main factor supporting the genetic background of isolated autism is a positive family history of autism/ASD. Syndromic autism is diagnosed in approximately 25% of autistic patients, and the genetic basis is identified significantly more often among patients with intellectual disabilities. The same conclusion reflects IMD – autistic features reported among patients with IMD are secondary to intellectual disability. Thus, all neurometabolic diseases presenting with intellectual disability may meet the criteria for ASD diagnosis.
The most important factor is that some genetic (metabolic) conditions could be initially misdiagnosed as having autism spectrum disorders, putting them at risk for unnecessary testing and treatments. Mucopolysaccharidosis (MPS) type III (Sanfilippo syndrome), unlike the other MPS that present with extensive somatic involvement, typically presents with mainly cognitive and neurological features [32]. Between the ages of 1 and 3 years, a slowing or plateauing of cognitive development becomes apparent; often speech is more noticeably affected than other cognitive functions. From the age of 3–4 years, progressive cognitive deterioration and the emergence of behavioural difficulties, including hyperactivity, impulsivity, anxious behaviours, and autistic-like behaviours, is observed. It can be difficult for the clinician to distinguish MPS III behavioural difficulties from autism spectrum disorders and/or attention deficit hyperactivity disorder (ADHD), thus contributing to diagnostic delay [32].
Also, the presence of inborn error of metabolism does not exclude the existence of autistic features, but it is not a causative relationship. Autistic features co-existing with glycogen storage disease type IXa or MPS IVA (Morquio syndrome) were reported [7]. An accurate clinical evaluation is crucial, given the fact that the diagnosis of IMD is often clinical, supported by biochemical and genetic studies. Such a medical practice appears also more reasonable than a costly metabolic work-up.
Conclusions
Genetic consultation should be offered to all children presenting with autistic features.
There is no cause-effect relationship between autism spectrum disorders and inherited metabolic diseases; however, all neurometabolic diseases presenting with intellectual disability may meet the criteria for ASD diagnosis.
