Mitochondrial depletion syndromes (MDS) are severe disorders often presenting themselves in early infancy or childhood. They comprise of a variety of features including profound weakness, encephalopathy, seizures and liver failure. A particular form of a hepatocerebral depletion is known as Alpers-Huttenlocher Syndrome (AHS) characterised by progressive neuronal degeneration in childhood, explosive onset of seizures, developmental delay, cortical blindness and spasticity followed by fulminant liver failure and parieto-occipital cerebral atrophy . In AHS a depletion of the mtDNA is commonly observed, which is considered as a secondary phenomenon due to primary POLG mutations, which in turn leads to a defective system for oxidative phosphorylation (OXPHOS) . However, POLG mutations in these phenotypes are not exclusive to the observed mtDNA damage.
Currently, there is no clear link between a particular POLG genotype and the resulting phenotype. However, with the characterisation of an increasing number of reported POLG mutations, patterns start to emerge. All AHS affected patients reported so far carry one of two linker mutations (p.A467T or p.W748S) in combination with either another linker mutation or a mutation located in the polymerase domain , whereas the p.A467T mutation is the most common mutation identified in POLG. It is present in all major POLG-related diseases: Alpers-Huttenlocher disease, ataxia-neuropathy syndromes and PEO.
Our patient showed a severe clinical phenotype and died due to valproate induced fatal acute liver failure. Analysis of the mtDNA content revealed a severe depletion in liver (approx. 90%), a less pronounced depletion in skeletal muscle (approx. 25%) and no depletion in fibroblasts. As a consequence, a combined respiratory chain defect involving complexes I, III and IV was measured in liver cells. In skeletal muscle, only complex IV showed a decreased activity suggesting that complex IV is the most vulnerable in mtDNA depletion syndromes. However, it is unknown which factors contribute to the tissue specificity of mitochondrial dysfunction in patients carrying POLG mutations. The finding of normal OXPHOS enzyme activities in our patient is also a common observation in other patients  and emphasises the need to investigate primary tissues as fibroblast analysis may give misleading results. The cellular mtDNA content may be an indicator of the underlying molecular mechanism linking genotype to phenotype and explaining the patient's acute liver failure.
Molecular genetic analysis of POLG revealed two linker region mutations, the c.1399G > A (p.A467T) and a novel splice site mutation c.1251-2A > T affecting the highly conserved splice acceptor site in intron 6. Analysis of the patient's parents confirmed that these mutations are present in trans in the patient. These findings are in good agreement with the observation that patients with two linker mutations exhibit a more severe clinical phenotype than patients carrying one linker and one polymerase domain mutation . Furthermore, detection of the primary mutations in POLG did not only confirm the clinical diagnosis of Alpers syndrome, but also allowed a reliable prenatal diagnosis for the parents in the following pregnancy (Figure 1A and 1B).
Several inborn errors of metabolism are known to represent a risk factor for severe idiosyncratic reactions to VPA, including liver toxicity . Many studies have focused on the interaction between VPA and mitochondrial function in general and mitochondrial disorders such as Alpers-Syndrome in particular, as conditions predisposing to severe VPA toxicity . Recent studies gave evidence that POLG mutations can lead to a range of clinical phenotypes which predispose to the development of fatal liver failure after exposure to VPA [15, 18]. Nevertheless, a single case report suggests that there may be mutations in the POLG gene associated with reversibility of the hepatotoxicity , The presented study extends the list of POLG mutations associated with VPA hepatotoxicity.