Polymerase Gamma: A True Story of Men Against a Gene
INTRODUCTION
Mitochondria play an important role in the generation of adenosine triphosphate via the electron-transport chain through oxidative phosphorylation. Mitochondrial dysfunction often leads to disorders that present with various neurologic, hepatic and muscular symptoms1. Mi-tochondrial disorders are infrequently diagnosed in India,
mainly because of the lack of advanced diagnostic facilities and molecular studies. However, with the increasing avail- ability and feasibility of genetic testing, it has now become possible to confirm these diagnoses – to guide the future management of affected children, as well as for accurate counselling and prenatal diagnosis in future pregnancies in their families2.
Mutations in the polymerase gamma gene (POLG), which codes the DNA polymerase enzyme in mitochondria, are associated with a clinical continuum of heterogeneous syndromes, ranging from infantile-onset epilepsies and liver failure to late-onset ophthalmoplegia and muscle weakness. Alpers disease, or progressive neuronal de- generation of childhood, which first received attention from Alpers in 1931 and was further described with its hepatic manifestation by Huttenlocher and Harding3-4, is
a rare mitochondrial disease characterized by its classic triad of refractory seizures, psychomotor regression, and hepatopathy5. Alpers Syndrome is one of the most severe phenotypes of polymerase gene mutation, and death usually occurs before 10 years of age.
CASE REPORT
A 7-year-old boy initially presented to the Emergency department with generalised tonic-clonic movement of his limbs. He had generalised clumsiness which had lasted for two years, and had difficult vision in bright lights. The developmental milestones were otherwise normal. He had no prior hospital admission. The patient was the third child of a non-consanguineous married couple. The birth history and perinatal history had been unremarkable, and his weight and height were between the third and fiftieth centiles.
The child was initially treated with benzodiazepines, phenytoin and levetiracetam. His EEG showed continuous generalised epileptiform discharges, hence midazolam infusion was started. A CT scan and MRI were normal (Fig 1), as was the CSF. In view of the super refractory status epilepticus and not being able to control the electrographic seizure activity, a general anaesthetic agent, isoflurane, was initiated. Burst suppression was achieved after 2 hours of initiation of isoflurane, this was then gradually tapered over a period of 48 hours. Other anticonvulsants Phenytoin, levetiracetam and valproate were optimised. Concurrent infections were treated accordingly. The child was discharged after a 4 week of hospital stay, and remained under regular follow up.
Two months later, the child was readmitted for repeated bouts of vomiting and lethargy. On examination, he had mild ptosis and external ophthalmoplegia, hypotonia of all 4 limbs and the liver was slightly enlarged. An EEG showed occipital spikes. The initial laboratory findings suggested acute liver failure, with AST and ALT levels of 244 IU/L and 168 IU/L, total and direct bilirubin of 4.4 mg/dL and 3.3 mg/ dL, and ammonia of 98 μg/dL respectively. An initial blood gas analysis test, with normal pH of 7.37 and bicarbonate of 25.8 mmol/L, was not suggestive of definite metabolic acidosis, although the lactate level was slightly elevated to 5.4 mmol/L. The prothrombin time was initially 2.5(INR) and over the course of time the INR gradually increased, along with the liver enzymes. An MRI Brain did not show any significant changes.
Drug levels were requested, to rule out any drug-induced cause for liver dysfunction. The serum phenytoin and serum valproate levels were normal. Ammonia reduction measures including sodium benzoate and carnitine were started. Plasmapheresis was initiated, in order to elimi- nate the valproate metabolites in the blood that can cause liver dysfunction. The serum lactate levels were progressively increasing. Numerous viral and autoimmune evaluations were performed that all returned as normal, and there were no remarkable findings in an imaging study. The lactate-to-pyruvate ratio was 20, and urine sent for GCMS suggested the possibility of lactic acidosis due to a mitochondrial disorder.
MR Spectroscopy (Figs 2, 3) did not show any elevated levels of lactate, and tandem mass spectroscopy results were normal. Therefore, a whole-exome sequencing analysis was sent for further evaluation. Meanwhile, the patient’s mental status became drowsy with hyperam- monemia, and he had become progressively jaundiced. He had multiple episodes of seizures in the form of myoclonic jerks and focal seizures, and had persistent ptosis and external ophthalmoplegia. An EEG showed generalised slowing. A liver transplant was not performed in view of the mitochondrial etiology and neurological involvement. The child died a few weeks later because of progressive liver failure. Two weeks postmortem, his genetic results showed he was positive for a polymerase gene mutation.
DISCUSSION
Alpers-Huttenlocher syndrome is a rare autosomal recessive disorder, caused by mutation in the polymerase gamma gene. The most common age of onset is between 2 and 4 years, with a range of 3 months to 8 years. Infants and children with Alpers-Huttenlocher syndrome are healthy until disease onset, although some have identified non-specific developmental delays. The age of onset is influenced, in part, by specific mutations within the polymerase gamma gene, other genes, and environmental factors such as intercurrent viral infections and certain medications like valproic acid. The classic clinical triad is developmental regression, hepatopathy and refractory seizures (Table 2).
Thus, the diagnostic criteria for Alpers-Huttenlocher syndrome were met in this patient; the classic clinical triad of refractory seizures, liver failure and developmental regression; elevated blood and CSF lactate; and an elec- troencephalogram showing multifocal spike-and-wave discharges. In addition, the diagnosis was confirmed via genetic analysis, which revealed polymerase-gamma (POLG) gene mutations.
The POLG gene encodes the mitochondrial DNA replicase protein, which is essential for maintaining the integrity of mitochondrial DNA. There are over 50 known mutations associated with Alpers-Huttenlocher syndrome and over 200 mutations of the POLG gene.
Alpers-Huttenlocher syndrome primarily affects organs that require large amounts of energy, and which are prone to oxidative damage, which include: the brain, peripheral nervous system, liver, and gastrointestinal tract.
Seizures are the most dramatic central nervous symptom of the syndrome. In about 50% of patients, seizures are the heralding symptom. Once seizures appear, the tempo of the disease becomes rapidly progressive, and death usually occurs within 4 years of disease onset. In other cases, disease progression is usually slower. The etiology for the variation in disease progression is unknown7.
In a situation in which a patient is placed on valproate, liver dysfunction usually begins within 2–3 months, but may be delayed by up to 6 months. Liver dysfunction is usually heralded by hypoglycaemia, decreased albumin synthesis, reduced synthesis of coagulation factors, and mild transaminase elevation. Early recognition of liver dysfunction may stop the progression to failure8,9.
The first association of the use of valproic acid and rapid onset of liver disease in a child with Alpers-Huttenlocher syndrome soon led to the understanding that the clinical variables associated with valproate-induced liver failure were in fact the clinical features of Alpers-Huttenlocher syndrome. Therefore, valproic acid (and divalproex sodium) have likely altered the natural history of Alpers- Huttenlocher syndrome, and may have given the impres- sion of a universally rapidly progressive disease8. Now that it is possible to rapidly identify patients with Alpers- Huttenlocher syndrome, and it is widely accepted that valproate is contraindicated in this disorder, an analysis of seizure frequency, duration, and medication use (without valproic acid exposure) needs to be performed in order to understand the natural history of disease progression without this variable.
Treatment of patients with Alpers-Huttenlocher syn- drome is limited to supportive care. Family education should be addressed as soon as the family is able to absorb the diagnosis. The holistic perspective of care should be pal- liative even if death is not imminent. This illness progresses to a fatal encephalopathy or liver failure, and varying levels of treatment can be addressed openly with the family. Sup- portive care will include the placement of a gastrostomy feeding tube for medication, hydration, and/or nutrition10.
SUMMARY
Awareness of mitochondrial disorders is essential, as there are no specific pointers other than raised lactate in concurrence with organ-specific dysfunction. An index of suspicion should be raised whenever any child is noted to have the constellation of symptoms of the hepato-cerebral or myopathic form, or even in cases of isolated liver disease. It is important to recognize Alpers-Huttenlocher syndrome to avoid administering medications that can predispose a patient to liver failure, particularly since liver transplantation is not appropriate in such a patient.
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