Should metabolic diseases be systematically screened in nonsyndromic autism spectrum disorders?

16 Sep

Metabolic disorders became a major point of discussion within the autism community a few years back. The upside was that a potentially important area of research (and not just within autism) was highlighted. The downside was that a lot of misinformation was propagated.

A lot of answers are still unknown precisely. The prevalence of metabolic disorders in autism, specifically mitochondrial disorders, was likely exaggerated by many, but that doesn’t make it an unimportant question. The question of how metabolic disorders fit into the etiology of autism is another open and valuable question.

The current study addresses the question of whether autistics should be routinely screened for metabolic disorders. On some very real level, I’m sure many people think that people should be screened for everything. If screening were fast, accurate, cheap and non-invasive, this would be a good point. But, this isn’t really the case. So the authors pose the question: Should metabolic diseases be systematically screened in nonsyndromic autism spectrum disorders?

The paper comes from a group at APHP, Reference Center for Inherited Metabolic Disease, Hôpital Robert Debré, Paris, France.

Here is the abstract:


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.

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.

They conclude that the prevalence of inherited metabolic disorders (IMD) in non-syndromic (i.e. those where an underlying condition is considered to be the cause of autism) autistics is about the same as for the general population (<0.5%) and that routine screening does not give insight into the cause of autism.

Here are a couple of paragraphs from the study:

Notably, a recent study pointed out that mitochondrial dysfunction may be involved in ASD [30]. In this report, plasma lactate determination was performed in a restricted sample of 69 patients with ASD. Twenty per cent of them displayed hyperlactatemia and 7% fulfilled the criteria for a disorder of oxidative phosphorylation (OXPHOS) [30]. This initial study has limitations as the autistic clinical phenotype was not well defined. More recently, a retrospective study of 25 patients with a primary diagnosis of nonsyndromic autism who were further determined to have enzyme- or mutation- defined OXPHOS deficiency showed that 96% of these patients actually exhibited clinical symptoms differentiating them from idiopathic autism [31]. These results suggest that careful clinical and biochemical reappraisal is warranted in patients with ASD initially considered as nonsyndromic, but also confirm that ASD patients with OXPHOS dysfunction often exhibit other symptoms such as microcephaly, marked motor delay, sensorineural deafness, oculomotor abnormalities, exercise intolerance, cardiomyopathy or renal tubular dysfunction. Accordingly, we decided not to screen for hyperlactatemia in our nonsyndromic ASD population. Furthermore, normal plasma lactic acid concentrations do not exclude the presence of a mitochondrial disorder [32], [33]. Recent reports emphasize a putative association between mitochondrial dysfunction and autism (for review see [34]) and highlight the role of brain energy metabolism dysfunction as an important target for future studies [35]. In ASD, as already emphasized for several neurodegenerative disorders [36], [37], [38], [39], mitochondrial dysfunction could be regarded as a secondary defect in brain energy metabolism.

They state that mitochondirial dysfunction is “secondary”, which I believe means they don’t see it as causative for autism. This is made more clear below:

The data reported here strongly support the view already stressed by others [20], [44] that systematic metabolic investigations are not contributive to the etiology of nonsyndromic ASD. On the other hand, early diagnosis and proper therapeutic intervention for some metabolic disorders causing nonsyndromic ASD may significantly improve the long-term cognitive and behavioral outcomes [20]. Therefore, a careful clinical evaluation, with cautious reappraisal of clinical signs, is crucial. Such a medical practice appears more reasonable than a costly systematic workup. Finally, a large population based prospective study assessing the benefits of routine metabolic screening in nonsyndromic ASD would be of great interest in the future to confirm our results.

They suggest that while discovering underlying metabolic disorders/dysfunctions can lead to beneficial treatments for those affected, they don’t shed light on the cause (etiology) of autism.

“Therefore, a careful clinical evaluation, with cautious reappraisal of clinical signs, is crucial. Such a medical practice appears more reasonable than a costly systematic workup. ”

I find the above very interesting. I’m sure that many in the alternative medical community would read that as approval of their less stringent diagnostic practices. To me it plays more into the idea that diagnosis of metabolic disorders can be as much an art as a science at times. To me, this means seeking out “one skilled in the art” (i.e. a metabolic specialist), rather than, say, a DAN doctor.

Here are a most of the references cited in the paragraphs above.

[30]Oliveira G, Diogo L, Grazina M, Garcia P, Ataide A, et al. (2005) Mitochondrial dysfunction in autism spectrum disorders: a population-based study. Dev Med Child Neurol 47: 185–189. Find this article online
[31]Weissman JR, Kelley RI, Bauman ML, Cohen BH, Murray KF, et al. (2008) Mitochondrial disease in autism spectrum disorder patients: a cohort analysis. PLoS One 3: e3815. Find this article online
[32]Debray FG, Lambert M, Chevalier I, Robitaille Y, Decarie JC, et al. (2007) Long-term outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases. Pediatrics 119: 722–733. Find this article online
[33]Touati G, Rigal O, Lombes A, Frachon P, Giraud M, et al. (1997) In vivo functional investigations of lactic acid in patients with respiratory chain disorders. Arch Dis Child 76: 16–21. Find this article online
[34]Rossignol DA, Frye RE (2011) Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry.
[35]Haas RH (2010) Autism and mitochondrial disease. Dev Disabil Res Rev 16: 144–153. Find this article online
[36]Moreira PI, Zhu X, Wang X, Lee HG, Nunomura A, et al. (2010) Mitochondria: a therapeutic target in neurodegeneration. Biochim Biophys Acta 1802: 212-220. pp. 212–220.
[37]Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, et al. (1998) Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93: 973–983. Find this article online
[38]Damiano M, Galvan L, Deglon N, Brouillet E (2010) Mitochondria in Huntington’s disease. Biochim Biophys Acta 1802: 52-61. pp. 52–61.
Mochel F, Haller RG (2011) Energy deficit in Huntington disease: why it matters. J Clin Invest 121: 493–499. Find this article online
[39] Mochel F, Haller RG (2011) Energy deficit in Huntington disease: why it matters. J Clin Invest 121: 493–499

3 Responses to “Should metabolic diseases be systematically screened in nonsyndromic autism spectrum disorders?”

  1. passionlessDrone September 16, 2011 at 16:43 #

    Hi Sullivan –

    A correction to this paper came out the other day. I hadn’t read either, have you read the correction?

    To me it plays more into the idea that diagnosis of metabolic disorders can be as much an art as a science at times.

    Nicely stated and part of the big problem I think that both ‘sides’ of this issue have a hard time understanding / admitting.

    I’ve wondered previously if different types of cells have different energy requirements, could we miss regionally specific mitochondria related problems by sampling where things are relatively easy (i.e., the blood and urine). I got to thinking about this while trying to reconcile the possible association between a dysregulated immune response and mitochondria problems with the brain specific regions in autism that seem to show evidence of an ongoing immune response.

    We have lots more art / science to go!

    – pD

  2. daedalus2u September 18, 2011 at 00:27 #

    The correction was for a misspelling of one of the author’s names. The correct spelling is:

    Odile Boespflug-Tanguy

  3. Christie Buchovecky October 9, 2011 at 18:02 #

    Hey guys, I know I’m late to the party for this one, but I just wanted to weigh in. If ever there was a controversial topic in autism that legitimately deserves further study, this is it.

    I just wanted to note that I agree with a lot of what pD said, but wanted to add that mitochondrial problems may be as much about ROS load as about energy requirements.

    Also, a major issue in this field is that everyone defines “metabolic disorder” slightly differently. This is in no small part due to the fact that, when discussed by doctors, metabolism tends to be more strictly defined as converting food to energy, while, when discussed by biochemists, metabolism is just the chemical reactions that break down (catabolism) organic matter or build new (anabolism) cellular components. Interestingly, the health profession also sometimes talks about “metabolites” in the more broad biochemical context, rather than the more strict energy-specific definition (metabolites of a drug are what is left when it has been broken down in the liver, for example).

    So, yes, a large subset of autism is likely caused by error in metabolism at some level, if you use the broader definition. A great example of this is Smith-Lemil-Optiz syndrome, which presents with syndromic autism and is caused by a mutation in a gene that effects the anabolism of cholesterol, halting the process at a specific step leading to both a lack of cholesterol that is needed in cell membranes, hormone production, and many other things, as well as a toxic buildup of the cholesterol precursor.

    However, I do agree with the authors, (and their work seems to support this well – from my quick reading, at least) that energy metabolism issues may exacerbate symptoms, but is unlikely to be a significant cause of autism. I do find it interesting that the researchers choose to focus on “nonsyndromic” ASDs; it seems fairly obvious to me that something as ubiquitous and significant as metabolism is unlikely to present as ASD alone (see the last sentence in the author’s own background).

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