Tuesday, September 8, 2015

Autism and inborn errors of metabolism

Asato MR, Goldstein AC, Schiff M. Autism and inborn errors of metabolism: how
much is enough? Dev Med Child Neurol. 2015 Sep;57(9):788-9.

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...

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 cystathionine-β-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...

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.

Courtesy of a colleague

1 comment:

  1. Schiff M, Benoist JF, Aïssaoui S, et al. Should metabolic diseases be systematically screened in nonsyndromic autism spectrum disorders? PLoS ONE 2011; 6: e21932.



    In the investigation of autism spectrum disorders (ASD), a genetic cause is found in approximately 10–20%. Among these cases, the prevalence of the rare inherited metabolic disorders (IMD) is unknown and poorly evaluated. An IMD responsible for ASD is usually identified by the associated clinical phenotype such as dysmorphic features, ataxia, microcephaly, epilepsy, and severe intellectual disability (ID). In rare cases, however, ASD may be considered as nonsyndromic at the onset of a related IMD.


    To evaluate the utility of routine metabolic investigations in nonsyndromic ASD.

    Patients and Methods

    We retrospectively analyzed the results of a metabolic workup (urinary mucopolysaccharides, urinary purines and pyrimidines, urinary creatine and guanidinoacetate, urinary organic acids, plasma and urinary amino acids) routinely performed in 274 nonsyndromic ASD children.


    The metabolic parameters were in the normal range for all but 2 patients: one with unspecific creatine urinary excretion and the other with persistent 3-methylglutaconic aciduria.


    These data provide the largest ever reported cohort of ASD patients for whom a systematic metabolic workup has been performed; they suggest that such a routine metabolic screening does not contribute to the causative diagnosis of nonsyndromic ASD. They also emphasize that the prevalence of screened IMD in nonsyndromic ASD is probably not higher than in the general population (<0.5%). A careful clinical evaluation is probably more reasonable and of better medical practice than a costly systematic workup.