Lathosterolosis, cholesterol and autism?

Although intrigued by the findings reported by Pier Luigi Calvo and colleagues [1] describing a "unique case" potentially linking liver functions and cognitive functions with a hat-tip to the presentation of autistic behaviours, I'll readily admit that I am way out of my comfort and competence zones when discussing this paper so please be ready with that pinch of salt.

How do you like your eggs in the morning? @ Wikipedia 

As per what the paper and accompanying press release (see here) indicate, this was a case report of a young girl diagnosed with lathosterolosis [2] - a rare inborn error of metabolism characterised by the accumulation of 5α-Cholest-7-en-3β-ol (lathosterol), an intermediate compound tied into the metabolism of cholesterol - and her changing clinical presentation following a liver transplant. The authors note that this was the "only surviving patient with lathosterolosis" such is the seriousness of the condition.

In case you want the real heavy biochemistry, have a look at the paper by Brunetti-Pierri and colleagues [3] discussing all-things lathosterolosis and in particular, the crucial part played by the enzyme 3-beta-hydroxysteroid-delta-5-desaturase (sterol-C5-desaturase or SC5D) in the condition.

The suggestion from the Calvo study that "timely liver transplantation might arrest the progression of neurological damage caused by diseases related to problems with cholesterol production" whilst sounding pretty invasive is nonetheless, of potential importance to a wider area of research. The details of outcome describing "a complete biochemical recovery, an arrest of mental deterioration and a stable MRI picture" at 5-year follow-up are nothing short of remarkable.

As far as I can make out, quite a bit of the discussion where autism or autistic behaviours is mentioned revolves around the correlation between issues with social interaction, exploration of her environment and cholesterol biosynthesis, and what happened when cholesterol levels were normalised as a consequence of the liver transplant. Certainly this is not the first time that cholesterol and autism have been mentioned in the same breath together. In a post going back some years now, I talked about the various research in this area, and specifically a condition called Smith-Lemi Opitz syndrome (SLOS) which represents the prototypical 'issues with cholesterol formation can affect physiology and behaviour' condition. The paper by Sikora and colleagues [4] titled: 'The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome' kinda hinted at the link between SLOS and the presentation of autism/autistic behaviours, compounded by other data [5] (open-access here) correlating low cholesterol levels and autism in some cases. Remember: autisms not autism.

Just in case anyone gets the wrong idea about my interpretation of this research, I'm not for one minute suggesting that a liver transplant is indicated for cases of autism outside of when medically required. As the study author notes: "We were dealing with a unique case—literally, as the child is the only known surviving patient with the condition—so it is difficult drawing inferences of broader significance". That however the liver provides an indispensable array of functions (see here too) might however mean that any whole body research approach applied to autism (not just looking at the grey/pinkish matter floating in the skull) might include some basic analysis of it's function too. As noted from other research in this area such as that included in the paper by Horvath & Perman [4] discussing sulphation (sulfation) capacity of the liver and cases of autism, there is potentially more to do in this area. Other work by Wakefield and colleagues [6] (open-access here) suggesting that: "hepatic encephalopathy represents a prototypic afferent gut–brain interaction that may provide insight into other encephalopathic states that have been linked to extra-cranial pathology", might also provide some food for thought in this area too.

Finally, continuing the possibility of a cholesterol connection to some autisms, I'll refer you back to some very interesting data talked about on the SFARI blog last year (2013) on the possibility of statins and cholesterol supplements as areas of future investigation (with no medical or clinical advice given or intended). A hat-tip also goes to Peter over at the Epiphany blog and his series of articles on statins and autism too with some accompanying information about side-effects too [7].

Music to close. And after recently watching the documentary on the reformation of the Stone Roses, a pretty famous song... Waterfall and memories of growing up listening to the Stone Roses the first time around come flooding back. 

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[1] Calvo PL. et al. Liver transplantation in defects of cholesterol biosynthesis: the case of lathosterolosis. Am J Transplant. 2014. March 12.

[2] Krakowiak PA. et al. Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency. Hum Mol Genet. 2003 Jul 1;12(13):1631-41.

[3] Brunetti-Pierri N. et al. Lathosterolosis, a Novel Multiple-Malformation/Mental Retardation Syndrome Due to Deficiency of 3β-Hydroxysteroid-Δ5-Desaturase. Am J Hum Genet. Oct 2002; 71(4): 952–958.

[4] Sikora DM. et al. The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome. Am J Med Genet A. 2006 Jul 15;140(14):1511-8.

[5] Horvath K. & Perman JA. Autism and gastrointestinal symptoms. Curr Gastroenterol Rep. 2002 Jun;4(3):251-8.

[6] Wakefield AJ. et al. Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands. Aliment Pharmacol Ther. 2002 Apr;16(4):663-74.

[7] Finegold JA. et al. What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice. Euro J Preventive Cardiology. 2014;  March 12.

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Calvo, P., Brunati, A., Spada, M., Romagnoli, R., Corso, G., Parenti, G., Rossi, M., Baldi, M., Carbonaro, G., David, E., Pucci, A., Amoroso, A., & Salizzoni, M. (2014). Liver Transplantation in Defects of Cholesterol Biosynthesis: The Case of Lathosterolosis American Journal of Transplantation DOI: 10.1111/ajt.12645

Cholesterol levels in autism: Vader or Skywalker?

Cholesterol is a substance with a bad reputation. Blamed for everything from causing an increased risk of coronary heart disease to upping the risk of stroke via things like the very curiously titled metabolic syndrome, high total cholesterol levels are the Darth Vader of health, the dark side incarnate (at least episode IV & V dark side). As a result, modern society has been mobilised to do everything it can to reduce cholesterol; be it through food, medication, or exercise.

I have discussed the concept of risk quite a few times on this blog and how risk, whilst generally important, takes little account of our individual differences and circumstances. I don't feel that I am suitably qualified to contribute too much to any general debate about cholesterol and health, although my reading around this topic would perhaps suggest that the relationship between cholesterol and health is perhaps not as simple as many people might believe; a point highlighted by this recent post in Scientific American. Indeed Anakin Skywalker (episodes II, III and VI) over Darth Vader might be a better description of cholesterol: a bit of good and a bit of the dark side.

There are a few findings emerging in the area of cholesterol and developmentally-defined conditions which are worthy of some comment, some of which have already been discussed in the blogosphere. Fairly recently cholesterol featured in a post about chronic illness risk and autism. I will at this point repeat my well-chanted mantra: no medical advice is intended or given and please consult with your physician before making any changes to any dietary or medication regime.

Not surprisingly quite a bit of the literature on cholesterol and autism focuses on lifestyle issues like being overweight / levels of obesity and the possible physical side-effects from various medications associated with autism spectrum conditions. Whilst not wishing to downplay such health inequalities, I will instead focus on a few other areas of interest: measured levels of cholesterol and autism's association with other cholesterol-linked conditions.

When it comes to measured cholesterol levels in autism, there are a few, mixed trends appearing including this one pointing towards higher total cholesterol levels and higher low-density lipoprotein (LDL) levels (LDL = the 'bad' cholesterol) in a small trial of people with Asperger syndrome. This is contrasted with this study reporting values from children with autism where no significant difference was noted in either total or LDL levels compared to controls. This study based on samples from the AGRE dataset, found that about a fifth of participants with autism studied actually had low levels of cholesterol, defined as below the 5th centile in population terms. There are some obvious differences between these studies in terms of age, diagnosis and ethnicity which perhaps should be kept in mind before getting too carried away. One should perhaps also realise that measuring cholesterol on its own might mean very little without any other correlations related to symptom presentation or other health-related factors going back to metabolic syndrome.

One condition linked to cholesterol seems to crop up quite a lot in the various searches: the association between autism and Smith-Lemli Opitz syndrome (SLOS). SLOS is a genetic condition which biochemically, is characterised by a failure to make enough cholesterol and the subsequent knock-on effects this has. Interestingly, vitamin D is synthesised from cholesterol, going back to my previous post on the sunshine chemical. The limited research on vitamin D status in SLOS is however a little mixed regarding any deficiency being potentially present.

There is quite a lot of evidence for the appearance of autism or rather autistic symptoms occurring in many cases of SLOS, although as per the study previously highlighted by Tierney and colleagues, the reverse - SLOS appearing in many cases of autism - does not appear to be true. Having said that in those cases of autism where cholesterol is low, discussions have centred on the use of cholesterol supplements to increase circulating levels. Given that Mr Vader reputation for cholesterol, many people might find the idea of giving cholesterol slightly counter-intuitive to our modern-day health messages. This is probably why, at the time of writing, there is a bit of a hole in the research literature when it comes to cholesterol supplementation for autism. I did find this article reviewing its potential use and there are apparently trials on-going with regards to its potential effectiveness for cases of autism. This paper (full-text) again featuring Elaine Tierney offers a few other ideas. We wait and see what they report.

I don't want anyone to assume that from this post I am anti- anti-cholesterol because I am not (?). I do however believe that our modern-day relationship with cholesterol, like so many other things, is complicated. It was not so long ago for example that we were talking about violent deaths being associated with the lowering of cholesterol, in particular suicide attempts and low cholesterol in things like bipolar disorder, something which has resurfaced in discussions this year. Perhaps counter to my previous posts trying to assert the importance of environment alongside genes to many conditions including cases of autism, here I suggest that genes are also potentially as important as environment when it comes to cholesterol and autism and perhaps lots of other things too.

So then, Vader or Skywalker?