Autism and inborn errors of metabolism: how much is enough?

The advent of methodologies for scanning the human genome at high resolution, coupled with the growing sophistication of copy number variation studies, has increased the diagnostic yield in the medical work-up of autism spectrum disorders (ASDs). Notably, the use of chromosomal microarray as a first-tier testing in clinical cohorts allows identification of clinically relevant chromosomal abnormalities in about 10% of individuals with ASD. Similarly, exome sequencing has been shown to contribute to the identification of rare meaningful variants in a substantial proportion of patients with ASD. Recent reports emphasized the causal role of inborn errors of metabolism (IEMs) in autism, suggesting that some IEMs would be a preventable cause of autism. Exome sequencing has improved the ability to unravel recessive diseases in patients with ASD, especially in consanguineous families. Among the mutated genes, some are already known to cause IEMs, such as aminomethyltransferase (AMT), which is targeted in glycine encephalopathy. Mutations in branched chain ketoacid dehydrogenase kinase (BCKDK) gene led to the discovery of BCKDK deficiency. However, such pioneering discoveries should not modify the existing clinical reasoning about the relationship between ASD and IEMs. In some IEMs, autism or more commonly features of autism, represent one of the presenting symptoms of an underlying disease which often includes multi-organ involvement. It is difficult to supply an exhaustive and up-to-date list of IEMs associated with features of autism as demonstrated by the aforementioned reports. Conversely, very few IEMs may be associated with isolated autism as a prominent feature, particularly at the onset of the disease. For example, features of autism are observed in untreated phenylketonuria. Similarly, young children affected with classical homocystinuria due to cystathionineb-synthase deficiency may initially present with isolated autistic features. The same is true at the onset of mucopolysaccharidosis type III (MPS III, Sanfilippo disease). Nevertheless, with time, patients with MPS III often present with progressively severe behavior troubles and subtle signs of slowly progressing cognitive dysfunction, with developmental regression leading to severe encephalopathy. These rare IEMs, for which autism is a presenting symptom, could justify a minimal metabolic screening in individuals with ASD, especially because some of these IEMs can be treated. However, in a retrospective study of 274 nonsyndromic patients with ASD, we have shown (as already stated by others) that the diagnostic yield of such a work-up was very low. Of note, in the two reports the clinical picture was quite specific. First, the patients were from consanguineous families. Second, they displayed several symptoms in addition to autism. The patient with AMT deficiency exhibited intellectual disability, mild dysmorphology, and epilepsy with a burst suppression pattern on EEG (characteristic of glycine encephalopathy). The BCKDK-deficient patients exhibited cataracts, seizures, and intellectual disability. Thus, although the findings in AMT and BCKDK deficiencies represent a major advance towards the development of targeted therapies, they likely involve a selected population of patients. This line of reasoning may be consistent with the low diagnostic yield of exome sequencing in identifying IEMs in large series of patients with nonsyndromic ASD thereby confirming the low yield of metabolic investigations in such patients. This may be modulated by data on TMLHE (trimethyllysine hydroxylase epsilon) deficiency, which may act as a susceptibility factor for autism. A deletion of exon 2 of the X-linked TMLHE gene (first enzymatic step of endogenous carnitine biosynthesis) was found in nonsyndromic children with autism. While this TMLHE deletion occurred in the same frequency in control males versus males with ASD in simplex families, it was found with a 2.85-fold higher frequency in multiplex probands compared with all male controls. In summary, despite the recent identification of new IEMs as a cause of autism, the overall picture regarding the contribution of IEMs to autism remains relatively unaltered. It is unquestionably true that features of autism may be observed in a small portion of IEMs. However, this relationship is likely confined to a specific subset of rare patients with associated symptoms. For such patients, a detailed personal and family history along with careful physical examination searching for associated specific signs are crucial as they may guide the clinician in the decision to perform a metabolic work-up. Conversely, while recent large-scale exome sequencing studies emphasized the central role of synapse formation and maintenance, axonal pathfinding, and neurogenesis, they did not provide any new evidence for the role of cellular metabolic pathways. Such molecular findings provide strong supportive evidence for the already recommended clinical practice not to routinely screen for IEMs in nonsyndromic patients with ASD.