POLG-Related Neurological Disease

POLG-related disease is a group of mitochondrial DNA depletion and deletion disorders from variants in POLG (mitochondrial DNA polymerase gamma), the commonest cause of inherited mitochondrial disease in many populations. Phenotypes include Alpers-Huttenlocher syndrome, ataxia neuropathy spectrum (SANDO, MIRAS), myoclonic epilepsy myopathy sensory ataxia, and progressive external ophthalmoplegia. Inheritance is autosomal recessive (rare dominant forms).

Pathophysiology. Impaired mitochondrial DNA replication causes depletion or multiple deletions, with failure of neurons, liver and muscle.

Alpers syndrome: infantile or childhood refractory focal seizures and status epilepticus (often occipital), developmental regression, liver failure (often triggered by valproate), and cortical blindness. Ataxia neuropathy: sensory ataxic neuropathy, dysarthria, ophthalmoplegia, epilepsy, and migraine in adolescents or adults. Other findings are myopathy, parkinsonism, premature ovarian failure and psychiatric disease.

Red flags.

• Refractory epilepsy with liver dysfunction.
• Any exposure to valproate in a patient with suspected POLG disease.

Genetic testing of POLG (sequencing, with large deletion analysis) is the key test. EEG shows occipital spikes and focal discharges. MRI shows occipital cortical lesions, thalamic and cerebellar change. Serum lactate, liver tests, CSF protein, muscle biopsy (ragged red fibres, COX negative fibres, mitochondrial DNA depletion). Nerve conduction studies show sensory axonal neuropathy.

Differential diagnosis.

• Other mitochondrial disease (MELAS, MERRF, Leigh), Friedreich ataxia.
• Autoimmune encephalitis and infective encephalitis.
• Epilepsy with other genetic cause, Wilson disease and metabolic liver disease.

Avoid sodium valproate, which can precipitate fatal liver failure in POLG disease. Test for POLG before valproate in children with suspected mitochondrial or unexplained epilepsy.

Seizures. Levetiracetam 500 to 1500 mg twice daily (children 10 to 30 mg/kg twice daily), clobazam, topiramate, or others, with treatment of status epilepticus using benzodiazepines, then non-valproate drugs, and anaesthetic agents in refractory cases. Avoid prolonged propofol infusion.

Supportive. Nutrition, physiotherapy, hearing and vision support, physical therapy, treatment of diabetes (avoid metformin), liver care and management of dysautonomia. Coenzyme Q10 has limited benefit.

Ovarian failure. Hormone replacement.

Monitoring. Liver tests, seizure control, development and cardiac function.

Referral and escalation. Refer to mitochondrial disease services, epilepsy and genetics.

Special groups. Genetic counselling and prenatal diagnosis for families.