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To save any charges of plagiarism, my main reference for this paper is the excellent review article by Mary Kay Koenig* (open-access) on the presentation of mitochondrial disorders in childhood, which at a recent visit to the dentist of all places, I actually managed to read in detail and make some (semi-) legible notes.
So here goes.
I have already set some of the scene for mitochondria and their important effects on our lives in a few previous post looking at high lactate levels in cases of autism (see here) and also detailing some interesting midi-chlorian, sorry mitochondrial findings in relation to chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) (see here). Aside from the detail that approximately 20% of children with autism are estimated to present with high lactate levels, I introduced some of the ways and means that mitochondria work and in particular, their primary energy production aim.
It's in your D-D-DNA
The first thing to note about mitochondria is that they contain their own DNA, and most of it (all of it?) comes from your mother. Dad's sperm it seems, does not stand a chance in the most part. This distinction from nuclear DNA, is an important one, particularly to things like the science of molecular phylogenetics. It also means that one can to some extent distinguish between mitochondrial issues as a consequence of mitochondrial DNA (mtDNA) and those as a result of issues with nuclear DNA. As Dr Koenig notes: "the majority of cases of mitochondrial disorders in children result not from mitochondrial DNA mutations, but from nuclear DNA mutations". That being said, mtDNA has been implicated in cases of autism as per this paper by Napoli and colleagues** (open-access).
The next thing worth pointing out is that there is a symbiotic relationship between mitochondria and our cells. Mitochondria provide usable energy to the cell but the cell also nurtures the mitochondria with proteins and nutrients it needs too. A sort of 'you scratch my back and I'll scratch yours' relationship.
Processes and signs
OK, the processes involved is next in line. There are lots, but the electron transport chain is the primary one attached to mitochondrial dysfunction, all related to the production of adenosine triphosphate (ATP). ATP really is the bees knees when it comes to energy which cells need and use (as in the end product of cellular respiration). A shortage in the supply of ATP means that cells are not going to be able to complete their function optimally.
When it comes to the presentation of paediatric mitochondrial disorders, there are some interesting stats about the body systems most frequently showing signs and symptoms. To quote from the good Dr Koenig: "Approximately 45% of children present with neurologic signs" ranging from hypotonia to seizures. Additionally: "20% of patients demonstrate intellectual dysfunction or psychiatric disturbances". There are quite a few more somatic presentations in terms of liver and cardiac presentation but these seem to be slightly less frequently reported in the general literature apparently.
Diagnosis and assessment
Diagnosis of a mitochondrial disorder is not, it seems, totally straight forward. Without trying to make too much fuss, it also seems very 'spectrum-y' to me, in terms of the definition and laboratory diagnosis of a mitochondrial dysfunction which relies on various disciplines doing their diagnostic stuff and coming together to make the diagnosis.
Lactic acidosis is an important clinical finding, which includes measurement of plasma lactate as per that 1 in 5 kids with autism with high lactate levels. Lactic acidosis is all about what happens when there are low levels of ATP (that golden energy source) and how the body tries to compensate via up-regulation of glycolysis which in turn leads to an excess of pyruvate, which itself might lead to elevated levels of the amino acid alanine or lactate. As well as looking at lactate, one could perhaps therefore see some merit in looking at levels of pyruvate and alanine too.
Outside of just looking in blood/plasma, there is also some suggestion that looking at lactate levels in the brain might also be a good idea, as per the use of proton magnetic resonance spectroscopy. There are other potential markers and mediums to work with including lactate levels in urine and cerebrospinal fluid (bearing in mind how invasive this is) and muscle biopsy to look for ragged red muscle fibres using light microscopy. That alongside looking for mutations in nuclear and mitochondrial DNA. Indeed in saying all this, quite a nice roadmap of where and what to look at with autism and mitochondrial disorders in mind was provided by Weissman and colleagues*** (open-access) noting the high prevalence of gastrointestinal symptoms and indeed some more recent research**** including Dr Koenig on the authorship team.
I'm going to finish this very descriptive post at this point with a few choice pearls of wisdom from Dr Koenig. First, unexplained elevations of lactate in any medium "should raise suspicions for a mitochondrial disorder". Second, "mitochondrial disorders are progressive". Don't assume a one-off analysis rules anything out. Finally, "a mitochondrial disorder should be considered in any child presenting with nonspecific signs such as ... learning disorders [and] epilepsy".
'Nuff said (for now).
* Koenig MK. Presentation and diagnosis of mitochondrial disorders in children. Pediatr Neurol. 2008; 38: 305-313.
** Napoli E. et al. Evidence of reactive oxygen species-mediated damage to mitochondrial DNA in children with typical autism. Molecular Autism 2013; 4:2.
*** Weissman JR. et al. Mitochondrial disease in autism spectrum disorder patients: a cohort analysis. PLoS ONE. 2008; 3: e3815.
**** Bhardwaj J. et al. Impaired gastric emptying and small bowel transit in children with mitochondrial disorders. J Pediatr Gastroenterol Nutr. 2012; 55: 194-199.
***** Frye RE. et al. Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Translational Psychiatry. January 2013.
Koenig, M. (2008). Presentation and Diagnosis of Mitochondrial Disorders in Children Pediatric Neurology, 38 (5), 305-313 DOI: 10.1016/j.pediatrneurol.2007.12.001