Sodium valproate is a successful and frequently used first line therapy for a variety of different epileptic seizures and syndromes. Its use in very young patients with neurodevelopmental delay and epilepsia partialis continua has been questioned on the grounds that it may precipitate a neurometabolic decompensation in those with Alpers–Huttenlocher disease, leading to irreversible liver failure.6
Orthotopic liver transplantation has been attempted in patients with valproate induced liver failure, some of whom have later been shown to have Alpers–Huttenlocher disease.9,10
Although successful engraftment was achieved in most patients, they invariably died a short time later following progressive neurological deterioration. Consequently, valproate induced liver failure has been considered a contraindication to orthotopic liver transplantation, and this was the case for our patient. Fortunately, his liver failure slowly reversed and 2 years on his epilepsy has been successfully managed without neurological decline. He has an unusual genotype with four different substitutions and this may have influenced the clinical course of his disease. The A467T mutation is known to lower DNA binding affinity and catalytic efficiency of POLG1
but the role of the other substitutions is less clear. However, the E1143G mutation has been shown to partially rescue the deleterious effects of the W748S mutation (also associated with Alpers–Huttenlocher disease as well as ataxia and peripheral neuropathy), suggesting it may have a disease modifying role.12
The Q879H and T885S substitutions have not been reported in controls, but in the presence of two confirmed mutations it is difficult to be certain of their precise role in the disease pathogenesis. Both occur within the polymerase domain of POLG1
, a region of the gene specifically affected in Alpers–Huttenlocher disease (http://tools.niehs.nih.gov/polg/index.cfm
). Although neither amino acid substitution appears to be severe (amino acid remains hydrophilic), the Q879H substitution does affect a phylogenetically conserved site (amino acid position 885 appears to be less well conserved) and is therefore likely to be contributing to disease.
This case illustrates a clinically important variation in the phenotype of Alpers–Huttenlocher disease, where liver failure has previously been considered a pre-terminal event and invariably associated with an inexorable neurological decline.13
Sodium valproate played a key role in precipitating the liver failure in this case, but the mechanism for this drug effect remains elusive. Based on our observations, we recommend sequencing of POLG1
in children with valproate induced hepatic failure, particularly as identification of the E1143G mutation may indicate a more favourable outcome. Furthermore, we advise that, particularly in young children (<3 years old) with aggressive focal epilepsy, the POLG1
gene should be sequenced before commencing sodium valproate therapy. In situations where this is not possible, then serum lactate, ammonia and liver function should be closely monitored.
- Alpers–Huttenlocher syndrome (AHS) is characterised by psychomotor retardation, intractable epilepsy and liver failure.
- AHS is due to mutations in a nuclear gene (POLG), encoding a polymerase necessary for the replication and repair of mitochondrial DNA.
- In the case described here sodium valproate induced hepatic failure which was reversible.